Substituted amino carboxylic acids

ABSTRACT

Disclosed are compounds and pharmaceutically acceptable salts of formula (I):  
                 
 
     which are useful in the treatment of metabolic disorders related to insulin resistance, leptin resistance, or hyperglycemia.  
     Compounds of the invention include inhibitors of Protein tyrosine phosphatases, in particular Protein tyrosine phosphatase-1B (PTP-1B), that are useful in the treatment of diabetes and other PTP mediated diseases, such as cancer, neurodegenerative diseases and the like. Also disclosed are pharmaceutical compositions comprising compounds of the invention and methods of treating the aforementioned conditions using such compounds.

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority from U.S. ProvisionalApplication Ser. No. 60/466,870, filed Apr. 30, 2003, which isincorporated herein by reference, in its entirety.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The invention relates to substituted carboxylic acids and morespecifically to such compounds that are useful in the treatment ofsyndrome X (consisting of such abnormalities as obesity, dyslipidemia,hypercoagulation, hypertension, insulin resistance and leading to heartdisease and diabetes), obesity, diabetes, immunological disease,bleeding disorders and/or cancer. More specifically, it relates to suchcompounds that are capable of inhibiting Protein tyrosine phosphatases(PTPs), in particular Protein tyrosine phosphatase-lb (PTP-1B) which isa negative regulator of the insulin and leptin signaling pathway andimproves insulin-sensitivity.

[0004] 2. Description of the Related Art

[0005] This invention relates to a class of heterocycle substitutedcarboxylic acids that are inhibitors of various PTPs, in particularPTP-1B.

[0006] Protein tyrosine phosphatases are a large family of transmembraneor intracellular enzymes that dephosphorylate substrates involved in avariety of regulatory processes (Fischer et al., 1991, Science253:401-406). Protein tyrosine phosphatase-1B (PTP-1B) is anapproximately 50 kd intracellular protein, which is present in abundantamounts in various human tissues (Charbonneau et al., 1989, Proc. Natl.Acad. Sci. USA 86:5252-5256; Goldstein, 1993, Receptor 3:1-15).

[0007] Determining which proteins are substrates of PTP-1B has been ofconsiderable interest. One substrate which has aroused especial interestis the insulin receptor. The binding of insulin to its receptor resultsin autophosphorylation of the domain. This causes activation of theinsulin receptor tyrosine kinase, which phosphorylates the variousinsulin receptor substrate (IRS) proteins that propagate the insulinsignaling event further downstream to mediate insulin's variousbiological effects.

[0008] Seely et al., 1996, Diabetes 45:1379-1385 (“Seely”) studied therelationship of PTP-1B and the insulin receptor in vitro. Seelyconstructed a glutathione S-transferase (GST) fusion protein of PTP-1Bthat had a point mutation in the PTP-1B catalytic domain. Althoughcatalytically inactive, this fusion protein was able to bind to theinsulin receptor, as demonstrated by its ability to precipitate theinsulin receptor from purified receptor preparations and from whole celllysates derived from cells expressing the insulin receptor.

[0009] Ahmad et al., 1995, J. Biol. Chem. 270:20503-20508 used osmoticloading to introduce PTP-1B neutralizing antibodies into rat KRC-7hepatoma cells. The presence of the antibody in the cells resulted in anincrease of 42% and 38%, respectively, in insulin stimulated DNAsynthesis and phosphatidyinositol 3′ kinase activity. Insulin receptorautophosphorylation and insulin receptor substrate-1 tyrosinephosphorylation were increased 2.2 and 2.0-fold, respectively, in theantibody-loaded cells. The antibody-loaded cells also showed a 57%increase in insulin stimulated insulin receptor kinase activity towardexogenous peptide substrates.

[0010] Kennedy et al., 1999, Science 283: 1544-1548 showed that proteintyrosine phosphatase PTP-1B is a negative regulator of the insulinsignaling pathway, indicating that inhibitors of this enzyme arebeneficial in the treatment of Type 2 diabetes, which appears to involvea defect in an early process in insulin signal transduction rather thana structural defect in the insulin receptor itself. (J. M. Olefsky, W.T. Garvey, R. R. Henry, D. Brillon, S. Matthai and G. R. Freidenberg, G.R. (1988).) Cellular mechanisms of insulin resistance innon-insulin-dependent (Type II) diabetes. (Am. J. Med. 85: Suppl. 5A,86-105.) A drug that improved insulin sensitivity would have severaladvantages over traditional therapy of NIDDM using sulfonylureas, whichdo not alleviate insulin resistance but instead compensate by increasinginsulin secretion.

[0011] Ragab et al (2003, J. Biol. Chem 278(42), 40923-32) showed thatPTP 1B is involved in regulating platelet aggregation. Hence, inhibitionof PTP 1B can be predicted to have an effect on bleeding disorder, andcardiovascular disease.

[0012] Romsicki et al., (2003, Arch Biochem. Biophys 414(1), 40-50)showed that TC PTP is structurally and functionally very similar. A PTP1B inhibitor is very likely to also inhibit TC PTP. A knockout of the TCPTP gene produces a phenotype with impaired immune function. (You-Ten etal., 1997, J. Exp. Med. 186(5), 683-93). Hence, inhibitors of PTP 1B canbe predict to inhibit TC PTP and modulate immune response.

[0013] It has also been demonstrated that PTP-1B is a negative regulatorof leptin signaling (Kaszua et al. Mol Cell. Endocrinology, 195:109-118,2002). PTP-1B deficient mice show enhanced potency for exogenous leptinto suppress food intake (Cheng, et al. Developmental Cell 2:497-503,2002). Thus, inhibitors of PTP-1B augment the beneficial effects ofleptin on food intake, body weight regulation and metabolism, in normalindividuals and leptin resistant individuals.

[0014] Therefore, inhibitors of PTPs, and inhibitors of PTP-1B inparticular, are useful in controlling or treating obesity, syndrome X,Type 2 diabetes, in improving glucose tolerance, and in improvinginsulin sensitivity in patients in need thereof. Such compounds are alsouseful in treating or controlling other PTP mediated diseases, such asthe treatment of cancer, neurodegenerative diseases, immunologicaldisorders, bleeding and cardiovascular disorders, and the like.

SUMMARY OF THE INVENTION

[0015] In a broad aspect, the invention encompasses the compounds offormula (I) shown below, pharmaceutical compositions containing thecompounds and methods employing such compounds or compositions in thetreatment of diabetes and/or cancer.

[0016] The invention provides compounds of formula I:

[0017] and pharmaceutically acceptable salts thereof, wherein

[0018] R₁ is H, C₁-C₆ alkyl, phenyl(C₁-C₆)alkyl, or C₃-C₆ alkenyl;

[0019] R₆ and R₇ are independently H, C₁-C₆ alkyl, aryl(C₁-C₆)alkyl,(C₁-C₆)alkanoyl optionally substituted with 1 or 2 groups independentlyselected from amino, mono or dialkylamino, —NHaryl, —N(C₁-C₆ alkyl)aryl,and CO₂H, aryl(C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl, arylalkoxycarbonyl, heteroarylcarbonyl, heteroaryl, heterocycloalkyl carbonyl,—C(O)NH₂, —C(O)NH(C₁-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl,—C(═NH)NH₂, —C(═N—C(O)C₁-C₆ alkoxy)NH—C(O)C₁-C₆ alkoxy, or —SO₂-aryl,wherein the cyclic portions of each of the above are optionallysubstituted with 1, 2, 3, or 4 groups that are independently halogen,C₁-C₆ alkyl, C₁-C₆ alkoxy, NO₂, OH, CO₂H, CN, C₂-C₆ alkanoyl, NH₂,NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, haloalkyl or haloalkoxy;

[0020] R₈ is H, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkanoyl,wherein the aryl group is optionally substituted with C₁-C₄ alkyl, C₁-C₄alkoxy, halogen, NO₂, C₁-C₄ haloalkyl, or C₁-C₄ haloalkoxy;

[0021] R₂₀, R₂₁, R₂₂, and R₂₃ are independently selected from H,arylalkoxy, arylalkyl, halogen, alkyl, OH, alkoxy, NO₂, NH₂,NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, NH-aryl, N(C₁-C₄)alkyl-aryl,—NHSO₂-aryl, —N(C₁-C₄alkyl)SO₂aryl, wherein the aryl group is optionallysubstituted with 1, 2, 3, or 4 groups that are independently C₁-C₆alkyl, C₁-C₆ alkoxy, halogen, OH, NO₂, C₁-C₄ haloalkyl, C₁-C₄haloalkoxy;

[0022] L₂ is a bond, —O—(C₁-C₆)alkyl-, —(C₁-C₆)alkyl-O—,—N(R₈)C(O)—(C₁-C₄)alkyl-, —(C₁-C₄)alkyl-C(O)N(R₈)—;

[0023] L₃ is a bond, —(C₁-C₄)alkyl-O—, —O—(C₁-C₄)alkyl, —(C₁-C₄)alkyl-,—C₂-C₆ alkenyl-, —C(O)—, (C₁-C₄)alkyl-O—, —C(O)NH—, or —NHC(O)—;

[0024] L₄ is —(C₁-C₄)alkyl-, —S(O)_(u)—(C₁-C₄)alkyl-,—(C₁-C₄)alkyl-S(O)_(u)—(C₁-C₄)alkyl-, —C₂-C₆ alkenyl-, —C₁-C₆ alkoxyC₁-C₆ alkyl-, —O—C₁-C₆ alkyl-, —C(O)-(C₁-C₄)alkyl-, —(C₁-C₄)alkyl-C(O)—,C₁-C₆ alkyl-O—, —(C₁-C₄)alkyl-C(O)—(C₁-C₄)alkyl-, or—(C₁-C₄)alkyl-NR_(N)—(C₁-C₄)alkyl-;

[0025] wherein R_(N) represents (C₁-C₆)alkyl or hydrogen;

[0026] wherein u is 0, 1, or 2;

[0027] the A-ring is phenyl, naphthyl, isoindolyl, indolyl, pyridyl,thiazolyl, pyrimidyl, benzofuranyl, benzimidazolyl, or 1H-indazolyl eachof which is optionally substituted with 1, 2, 3, or 4 groups that areindependently, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,C₁-C₄ haloalkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, orN(C₁-C₆)alkyl(C₁-C₆)alkyl;

[0028] Q is -heteroaryl-(C₁-C₄)alkyl-aryl,-aryl-(C₁-C₄)alkyl-heteroaryl, heteroaryl, or aryl, each of which isoptionally substituted with 1, 2, 3, 4, or 5 groups that areindependently alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, C₁-C₆alkanoyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NH₂, NH(C₁-C₆)alkyl,N(C₁-C₆)alkyl(C₁-C₆)alkyl, phenyl, C₁-C₆ alkanoyl;

[0029] Q₂ is and H or aryl, wherein the aryl is optionally substitutedwith 1, 2, or 3 groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy,or halogen; and

[0030] Y and Y′ are independently a bond or —(C₁-C₄)alkyl-.

[0031] The compounds of formula I bind to PTPs, and in particular toPTP-LB. The interaction with the enzyme, specifically PTP-1B, preferablyresults in inhibition of the enzyme.

[0032] The invention also includes intermediates that are useful inmaking the compounds of the invention.

[0033] The invention also provides pharmaceutical compositionscomprising a compound or salt of formula I and at least onepharmaceutically acceptable carrier, solvent, adjuvant or diluent.

[0034] The invention further provides methods of treating disease suchas diabetes, syndrome X, cancer, immunological disease, bleedingdisorders, or cardiovascular disease in a patient in need of suchtreatment, comprising administering to the patient a compound orpharmaceutically acceptable salt of formula I, or a pharmaceuticalcomposition comprising a compound or salt of formula I.

[0035] In another aspect, the invention provides a method for inhibitingprotein tyrosine phosphatases, preferably PTP-1B, comprisingadministering a therapeutically effective amount of a compound offormula I.

[0036] In another aspect, the invention provides a method for treatingmetabolic disorders related to insulin resistance or hyperglycemia,comprising administering to a patient in need of such treatment atherapeutically effective amount of a compound of formula I.

[0037] The invention also provides the use of a compound or saltaccording to formula I for the manufacture of a medicament for use intreating diabetes or cancer or other diseases related to PTP.

[0038] The invention also provides methods of preparing the compounds ofthe invention and the intermediates used in those methods.

[0039] The invention also provides methods and compositions forcombination therapy of Type I and Type II diabetes. In theseembodiments, the invention provides formulations and pharmaceuticalcompositions, as well as methods for treating Type I and Type IIdiabetes with the compounds of formula I plus additional compounds andmedicaments as disclosed in more detail below. In these embodiments, themethods of the invention can comprise treatment methods for Type I andType II diabetes where the compounds of formula I are formulated with atherapeutically-effective amount of said additional compounds andmedicaments. In alternative embodiments, treatment methods of theinvention for Type-I and Type II diabetes comprise administration of theinventive compounds of formula I as disclosed herein concomitantly,simultaneously or together with a therapeutically-effective amount ofsaid additional compounds and medicaments.

DETAILED DESCRIPTION OF THE INVENTION

[0040] In another aspect, the invention provides compounds of formulaI-a, i.e., compounds of formula I, wherein,

[0041] R₆ and R₇ are independently H, C₁-C₆ alkyl, phenyl(C₁-C₆)alkyl,C₁-C₆ alkanoyl optionally substituted with 1 or 2 groups independentlyselected from amino, mono or dialkylamino, —NHphenyl, —N(C₁-C₆alkyl)aryl, and CO₂H, phenyl(C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl,benzyloxycarbonyl, benzimidazolylcarbonyl, benzofuranylcarbonyl,furanylcarbonyl, thiazolylcarbonyl, indolylcarbonyl, pyridyl, pyrimidyl,morpholinylcarbonyl, thiomorpholinylcarbonyl, thiomorpholinyl S,Sdioxide-carbonyl, piperazinylcarbonyl, piperidinylcarbonyl,pyrrolidinylcarbonyl, pyridylcarbonyl, pyrazolylcarbonyl, —C(O)NH₂,—C(O)NH(C₁-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, —C(═NH)NH₂,—C(═N—C(O)C₁-C₄ alkoxy)NH—C(O)C₁-C₄ alkoxy, —SO₂-phenyl, or—SO₂-naphthyl wherein the cyclic portions of each of the above areoptionally substituted with 1, 2, 3, or 4 groups that are independentlyhalogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, NO₂, OH, CO₂H, CN, C₁-C₆ alkanoyl,NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, C₁-C₄ haloalkyl or C₁-C₄haloalkoxy; and

[0042] Q is -benzofuranyl-(C₁-C₄)alkyl-phenyl,-pyridyl-(C₁-C₄)alkyl-phenyl, -dibenzofuranyl-(C₁-C₄)alkyl-phenyl,indolyl-(C₁-C₄)alkyl-phenyl, benzo[b]thienyl-(C₁-C₄)alkyl-phenyl,-phenyl-(C₁-C₄)alkyl-benzofuranyl, indolyl, phenyl,benzo[d][1,3]dioxolyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, dibenzothienyl,indolinyl, benzofuranyl, benzimidazolyl, or dibenzofuranyl, each ofwhich is optionally substituted with 1, 2, 3, 4, or 5 groups that areindependently alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, C₁-C₄haloalkyl, C₁-C₄ haloalkoxy, NH₂, NH(C₁-C₆)alkyl,N(C₁-C₆)alkyl(C₁-C₆)alkyl, phenyl or C₁-C₆ alkanoyl; and

[0043] Q₂ is H or phenyl.

[0044] In another aspect, the invention provides compounds of formulaI-b, i.e., compounds of formula I-a, wherein

[0045] R₁ is H, C₁-C₆ alkyl, benzyl, or allyl;

[0046] R₂₀, R₂₁, R₂₂, and R₂₃ are independently selected from H,benzyloxy, benzyl, halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, NO₂, NH₂,NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, NH-aryl, N(C₁-C₄)alkyl-aryl,—NHSO₂-phenyl, —N(C₁-C₄ alkyl)SO₂phenyl, wherein the phenyl group isoptionally substituted with 1, 2, 3, or 4 groups that are independentlyC₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH, NO₂, C₁-C₂ haloalkyl, C₁-C₂haloalkoxy;

[0047] the A-ring is phenyl, naphthyl, pyridyl, thiazolyl, pyrimidyl,isoindolyl, indolyl, benzofuranyl, benzimidazolyl, or 1H-indazolyl eachof which is optionally substituted with 1, 2, 3, or 4 groups that areindependently, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,C₁-C₄ haloalkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, orN(C₁-C₆)alkyl(C₁-C₆)alkyl;

[0048] L₂ is a bond, —O— (C₁-C₆)alkyl-, —(C₁-C₆)alkyl-O—, —N(R₈)C(O)—(C₁-C₄)alkyl-, —(C₁-C₄)alkyl-C(O)N(R₈)—; wherein

[0049] R₈ is H, (C₁-C₆)alkyl, phenyl(C₁-C₆)alkyl, phenyl(C₁-C₆)alkanoyl,wherein the phenyl groups are optionally substituted with 1, 2, 3, 4, or5 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, NO₂,C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy; and

[0050] L₃ is a bond, —(C₁-C₄)alkyl-O—, —O—(C₁-C₄)alkyl, —(C₁-C₄)alkyl-,or C(O).

[0051] In one aspect, the invention provides compounds of formula I-b-1,i.e., compounds of formula I-b wherein L₄ is —(C₁-C₄)alkyl-,—S(O)_(u)—CH₂—, or—(C₁-C₄)alkyl-S(O)_(u)—(C₁-C₄)alkyl-S(O)_(u)—(C₁-C₄)alkyl; and wherein uis 0, 1, or 2.

[0052] In another aspect, the invention provides compounds of formulaI-b-2, i.e., compounds of formula I-b wherein L₄ is —C₂-C₆ alkenyl-,—C₁-C₄ alkoxy C₁-C₄ alkyl-, —O—C₁-C₄ alkyl-, or C₁-C₄ alkyl-O—.

[0053] In still another aspect, the invention provides compounds offormula I-b-3, i.e., compounds of formula I-b wherein L₄ is—(C₁-C₄)alkyl-C(O)—, C₁-C₆ alkyl-O—, —(C₁-C₄)alkyl-C(O)— (C₁-C₄)alkyl-,or —(C₁-C₄)alkyl-NR_(N)—(C₁-C₄)alkyl-; wherein RN represents(C₁-C₆)alkyl or hydrogen.

[0054] In yet another aspect, the invention provides compounds offormula I-c, i.e., compounds according to any one of formulas I-b,1-b-1, 1-b-2, or I-b-3 wherein, the A-ring is isoindolyl, indolyl,benzofuranyl, benzimidazolyl, or 1H-indazolyl each of which isoptionally substituted with 1, 2, 3, or 4 groups that are independently,halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy,NO₂, NH₂, NH(C₁-C₆)alkyl, or N(C₁-C₆)alkyl(C₁-C₆)alkyl. In anotheraspect, the A-ring is unsubstituted.

[0055] In yet another aspect, the invention provides compounds offormula I-c-1, i.e., compounds according to any one of formulas I-b,1-b-1, 1-b-2, or I-b-3 wherein, the A-ring is pyridyl, thiazolyl, orpyrimidyl, each of which is optionally substituted with 1, 2, 3, or 4groups that are independently, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄haloalkyl, C₁-C₄ haloalkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, orN(C₁-C₆)alkyl(C₁-C₆)alkyl. In another aspect, the A-ring isunsubstituted.

[0056] In still another aspect, the invention provides compounds offormula I-d, i.e., compounds according to any one of formulas I-b,1-b-1,1-b-2, 1-c, or I-c-1, wherein R₁ is H.

[0057] In yet another aspect, the invention provides compounds offormula I-e, i.e., compounds of formula I-d, wherein R₂₀ and R₂₁ areboth hydrogen.

[0058] In another aspect, the invention provides compounds of formulaI-f, i.e., compounds according to any one of formulas I-b, 1-b-1,1-b-2,1-c, 1-d, or I-e, wherein Q₂ is hydrogen.

[0059] In another aspect, the invention provides compounds of formulaI-f-1, i.e., compounds according to any one of formulas I-b,1-b-1,1-b-2, 1-c, 1-d, or I-e, wherein Q₂ is phenyl.

[0060] In still another aspect, the invention provides compounds offormula I-g, i.e., compounds according to any one of formulas I-b,1-b-1,1-b-2, 1-c, 1-d, 1-e, 1-f, or I-f-1, wherein Y′ is a bond; and oneof R₂₂ and R₂₃ is hydrogen, while the other is hydrogen, NO₂, halogen,CF₃ or phenylalkoxy. In yet still another aspect, both R₂₂ and R₂₃ arehydrogen.

[0061] In another aspect, the invention provides compounds of formulaII, i.e., compounds of either formula I or formula I-b are compounds offormula II,

[0062] wherein

[0063] n is 0, 1, 2, 3, or 4; each R₁₀ is independently H, halogen,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NO₂, NH₂,NH(C₁-C₆)alkyl, or N(C₁-C₆)alkyl(C₁-C₆)alkyl;

[0064] Q is -benzofuranyl-(C₁-C₄)alkyl-phenyl,-pyridyl-(C₁-C₄)alkyl-phenyl, -dibenzofuranyl-(C₁-C₄)alkyl-phenyl,indolyl-(C₁-C₄)alkyl-phenyl, -phenyl-(C₁-C₄)alkyl-benzofuranyl, indolyl,phenyl, indolinyl, benzofuranyl, benzimidazolyl, or dibenzofuranyl, eachof which is optionally substituted with 1, 2, 3, 4, or 5 groups that areindependently C₁-C₆ alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, NH₂, NH(C₁-C₆)alkyl,N(C₁-C₆)alkyl(C₁-C₆)alkyl, or phenyl.

[0065] In another aspect, the invention provides compounds of formulaII-a, i.e., compounds of formula II, wherein

[0066] n is 0, 1, 2, or 3;

[0067] L₃ is a bond, —(C₁-C₄)alkyl-O—, —O—(C₁-C₄)alkyl, —(C₁-C₄)alkyl-,—C₂-C₆ alkenyl-, or —C(O)—;

[0068] R₁ is H, C₁-C₆ alkyl, phenyl(C₁-C₄)alkyl, or C₃-C₆ alkenyl; and

[0069] R₆ and R₇ are independently H, C₁-C₆ alkyl, aryl(C₁-C₆)alkyl,(C₂-C₆)alkanoyl, phenyl(C₁-C₆)alkanoyl, (C₁-C₆) alkoxycarbonyl,phenylalkoxycarbonyl, heteroarylcarbonyl, heteroaryl,heterocycloalkylcarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl,—C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, or —SO₂-aryl, wherein the cyclic groupsare optionally substituted with 1, 2, 3, or 4 groups that areindependently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, NO₂, OH, NH₂,NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, haloalkyl or haloalkoxy.

[0070] In another aspect, the invention provides compounds of formulaII-b, i.e., compounds of formula II-a, wherein R₂₀, R₂₁, R₂₂, and R₂₃are independently selected from H, phenylalkoxy, phenylalkyl, halogen,C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, orN(C₁-C₆)alkyl(C₁-C₆)alkyl.

[0071] In another aspect, the invention provides compounds of formulaII-c, i.e., compounds of formula II, or II-b, wherein R₁ is H, C₁-C₄alkyl, or benzyl, R₆ and R₇ are independently H, C₁-C₆ alkyl,phenyl(C₁-C₆)alkyl, (C₂-C₆)alkanoyl, phenyl(C₁-C₆)alkanoyl,(C₁-C₆)alkoxycarbonyl, benzyloxycarbonyl, benzimidazolylcarbonyl,benzofuranylcarbonyl, thiazolylcarbonyl, indolylcarbonyl,morpholinylcarbonyl, thiomorpholinylcarbonyl, thiomorpholinyl S,Sdioxide-carbonyl, piperazinylcarbonyl, piperidinylcarbonyl,pyrrolidinylcarbonyl, pyridylcarbonyl, pyrazolylcarbonyl, —C(O)NH₂,—C(O)NH(C₁-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, or —SO₂-phenylwherein the cyclic groups are optionally substituted with 1, 2, 3, or 4groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, NO₂,OH, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, C₁-C₂ haloalkyl orC₁-C₂ haloalkoxy.

[0072] In another aspect, the invention provides compounds of formulaII-d, i.e., compounds of formula II-c, wherein R₂₃ is H.

[0073] In another aspect, the invention provides compounds of formulaII-e, i.e., compounds of formula II-d, wherein R₂₂ and R₂₃ are both H.

[0074] In still another aspect, the invention provides compounds offormula II-f, i.e., compounds of formula II-c, II-d, or II-e, wherein L₂is a bond or —(C₁-C₄)alkyl; and L₃ is a bond, —(C₁-C₄)alkyl-O—, or—O—(C₁-C₄)alkyl, or —(C₁-C₄)alkyl-.

[0075] In yet another aspect, the invention provides compounds offormula II-g, i.e., compounds of formula II-c, II-d, or II-e, L₂ is abond or —(C₁-C₄)alkyl; and L₃ is a bond, —C₂-C₆ alkenyl-, or —C(O)—.

[0076] In still yet another aspect, the invention provides compounds offormula II-h, i.e., compounds of formula II-c, II-d, or II-e, wherein L₂is —O—(C₁-C₆)alkyl-, or —(C₁-C₆)alkyl-O—; and L₃ is a bond,—(C₁-C₄)alkyl-O—, or —O—(C₁-C₄)alkyl, or —(C₁-C₄)alkyl-.

[0077] In another aspect, the invention provides compounds of formulaII-i, i.e., compounds of formula II-c, II-d, or II-e, wherein L₂ is—O—(C₁-C₆)alkyl-, or —(C₁-C₆)alkyl-O—; and L₃ is a bond, —C₂-C₆alkenyl-, or —C(O)—.

[0078] In yet another aspect, the invention provides compounds offormula II-j, i.e., compounds of formula II-c, II-d, or II-e, wherein L₂is —N(R₈)C(O)—(C₁-C₄)alkyl-, or —(C₁-C₄)alkyl-C(O)N(R₈)—; wherein R₈ isH, (C₁-C₆)alkyl, benzyl, or phenyl-CO—, wherein the phenyl groups areoptionally substituted with C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, NO₂,CF₃, or OCF₃; and L₃ is a bond, —(C₁-C₄)alkyl-O—, or —O—(C₁-C₄)alkyl, or—(C₁-C₄)alkyl-.

[0079] In still another aspect, the invention provides compounds offormula II-k, i.e., compounds of formula II-c, II-d, or II-e, wherein L₂is —N(R₈)C(O)—(C₁-C₄)alkyl-, or —(C₁-C₄)alkyl-C(O)N(R₈)—; wherein R₈ isH, (C₁-C₆)alkyl, benzyl, or phenyl-CO—, wherein the phenyl groups areoptionally substituted with C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, NO₂,CF₃, or OCF₃; and L₃ is a bond, —C₂-C₆ alkenyl-, or —C(O)—.

[0080] In yet another aspect, the invention provides compounds offormula II-1, i.e., compounds of formula II-f, II-g, II-h, II-I, II-j,or II-k, wherein L₄ is —(C₁-C₄)alkyl-.

[0081] In another aspect, the invention provides compounds of formulaII-m, i.e., compounds of formula II-f, II-g, II-h, II-I, II-j, or II-k,wherein L₄ is —S(O)_(u)—CH₂—, wherein u is 0, 1, or 2.

[0082] In yet still another aspect, the invention provides compounds offormula II-n, i.e., compounds of formula II-f, II-g, II-h, II-I, II-j,or II-k, wherein L₄ is —(C₁-C₄)alkyl-S(O)_(u)—(C₁-C₄)alkyl, wherein u is0, 1, or 2.

[0083] In another aspect, the invention provides compounds of formulaII-o, i.e., compounds of formula II-e, wherein L₂ is a bond; and L₃ is abond.

[0084] In another aspect, the invention provides compounds of formulaII-p, i.e., compounds of formula II-e, wherein L₄ is —S(O)_(u)—CH₂—, or—(C₁-C₄)alkyl-S(O)_(u)—CH₂—; wherein u is 0, 1, or 2. In another aspect,u is 0. In yet another aspect, u is 2.

[0085] In another aspect, the invention provides compounds of formulaIII, i.e., compounds of formula II, II-a, II-b, II-c, II-d, II-e, orII-f, which has the following structure:

[0086] In still another aspect, the invention provides compounds offormula III-a, i.e., compounds of formula III, which has the formula:

[0087] In still another aspect, the invention provides compounds offormula III-b, i.e., compounds of of formula III or III-a wherein Q is-benzofuranyl-(C₁-C₄)alkyl-phenyl, -dibenzofuranyl-(C₁-C₄)alkyl-phenyl,indolyl, phenyl, benzofuranyl, benzimidazolyl, or dibenzofuranyl, eachof which is optionally substituted with 1, 2, 3, 4, or 5 groups that areindependently C₁-C₆ alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,CF₃, OCF₃, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, or phenyl.

[0088] In another aspect, the invention provides compounds of formulaIII-c, i.e., compounds of formula III-b, wherein R₁ is H, or C₁-C₆ alkyl(preferably H); R₆ is H; at least one of R₂₀ and R₂₁ is H; and L₄ is—(C₁-C₄)alkyl-, —S(O)_(u)—CH₂—, or —CH₂—S(O)_(u)—CH₂—; wherein u is 0,1, or 2.

[0089] In yet another aspect, the invention provides compounds offormula III-d, i.e., compounds of formula III-b or III-c, wherein L₄ is—CH₂—, —CH₂—S—CH₂— or —S—CH₂—. In another aspect, L₄ is —CH₂—S—CH₂— or—S—CH₂—.

[0090] In still another aspect, the invention provides compounds offormula III-e, i.e., compounds of formula III-b, III-c, or III-d,wherein R₇ is C₁-C₆ alkyl, (C₂-C₆)alkanoyl, (C₁-C₆) alkoxycarbonyl,—C(O)NH₂, —C(O)NH(C₁-C₆)alkyl, or —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl.

[0091] In yet still another aspect, the invention provides compounds offormula III-f, i.e., compounds of formula III-e, wherein R₇ is C₂alkanoyl or C₄ alkoxycarbonyl.

[0092] In yet another aspect, the invention provides compounds offormula III-G, i.e., compounds of formula III-b, III-c, or III-d,wherein R₇ is phenyl(C₁-C₄)alkyl, phenyl(C₁-C₆)alkanoyl,benzyloxycarbonyl, benzimidazolylcarbonyl, benzofuranylcarbonyl,thiazolylcarbonyl, indolylcarbonyl, morpholinylcarbonyl,piperazinylcarbonyl, piperidinylcarbonyl, pyrrolidinylcarbonyl, or—SO₂-phenyl wherein the cyclic groups are optionally substituted with 1,2, 3, or 4 groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, NO₂, OH, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, CF₃ orOCF₃.

[0093] In yet another aspect, the invention provides compounds offormula III-h, i.e., compounds of formula III-g wherein R₂₁ is H or NO₂.In another aspect R₂₁, is H.

[0094] In another aspect, the invention provides compounds of formulaIII-h-1, i.e., compounds of formula III-a, III-b, III-c, III-d, III-e,III-f, III-g, or III-h, wherein Q is -benzofuranyl-CH₂-phenyl,-dibenzofuranyl-CH₂-phenyl, or dibenzofuranyl.

[0095] In another aspect, the invention provides compounds of formulaIII-h-2, i.e., compounds of formula III-a, III-b, III-c, III-d, III-e,III-f, III-g, or III-h, wherein Q is indolyl, phenyl, benzofuranyl, orbenzimidazolyl.

[0096] In another aspect, the invention provides compounds of formulaIII-h-3, i.e., compounds of formula III, which have the formula:

[0097] In another aspect, the invention provides compounds of formulaIII-h-4, i.e., compounds of formula III-h-3, wherein R₁ is H; n is 1, 2or 3; L₃ is a bond, —CH₂—, or —(C₁-C₂)alkyl-O—; and each R₁₀ isindependently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, OCF₃, NO₂, NH₂,NH(C₁-C₆)alkyl, or N(C₁-C₆)alkyl(C₁-C₆)alkyl.

[0098] In yet another aspect, the invention provides compounds offormula III-i, i.e., compounds of formula III-a, III-b, III-c, III-d,III-e, III-f, III-G, or III-h, wherein Q is-benzofuranyl-(C₁-C₄)alkyl-phenyl, indolyl, phenyl, or dibenzofuranyl,each of which is optionally substituted with 1, 2, 3, 4, or 5 groupsthat are independently C₁-C₆ alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy,halogen, CF₃, OCF₃, NH₂, NH(C₁-C₆)alkyl, or N(C₁-C₆)alkyl(C₁-C₆)alkyl.

[0099] In another aspect, the invention provides compounds of formulaIII-j, i.e., compounds of formula III-i, wherein Q is-benzofuranyl-CH₂-phenyl, indolyl or dibenzofuranyl, each of which isoptionally substituted with 1, 2, 3, 4, or 5 groups that areindependently C₁-C₆ alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,CF₃, OCF₃, NH₂, NH(C₁-C₆)alkyl, or N(C₁-C₆)alkyl(C₁-C₆)alkyl. In anotheraspect, Q is unsubstituted.

[0100] In still another aspect, the invention provides compounds offormula III-k, i.e., compounds of formula III-j, wherein n is 0, 1, or2; L₃ is a bond; R₁ is H; and R₂₀ is H.

[0101] In another aspect, the invention provides compounds of formulaIII-1, i.e., compounds of formula III-j wherein L₄ is —CH₂—, —CH₂—S—CH₂—or —S—CH₂—. In another aspect, L₄ is —CH₂—S—CH₂— or —S—CH₂—.

[0102] In another aspect, the invention provides compounds of formulaIII-m, i.e., compounds of formula III-i, wherein R₇ is benzyl,phenyl(C₁-C₄)alkanoyl (in one aspect —C(O)phenyl, or —C(O)CH₂-phenyl,more preferably —C(O)phenyl), benzyloxycarbonyl, or —SO₂-phenyl whereinthe cyclic groups are optionally substituted with 1, 2, or 3 groups thatare independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, NO₂, OH, NH₂,NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, CF₃ or OCF₃.

[0103] In another aspect, the invention provides compounds of formulaIII-n, i.e., compounds of formula III-m, wherein R₇ is —SO₂-phenylwherein the phenyl group is substituted at the para position with eitheran halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, NO₂, or OH group.

[0104] In another aspect, the invention provides compounds of formulaIII-o, i.e., compounds of formula III-n, wherein R₇ isbenzyloxycarbonyl.

[0105] In another aspect, the invention provides compounds of formulaIV, i.e., compounds of formula III, which have the formula:

[0106] In still another aspect, the invention provides compounds offormula IV-a, i.e., compounds of formula IV, which have the formula:

[0107] In yet another aspect, the invention provides compounds offormula IV-a-1, i.e., compounds of formula IV or IV-a, wherein R₂₀ andR₂, are independently selected from H, benzyloxy, benzyl, halogen, C₁-C₆alkyl, OH, CL-C₆ alkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl,N(C₁-C₆)alkyl(C₁-C₆)alkyl, NH-phenyl, N(C₁-C₄)alkyl-aryl, —NHSO₂-phenyl,or —N(C₁-C₄ alkyl)SO₂phenyl, wherein the phenyl group is optionallysubstituted with 1, 2, 3, or 4 groups that are independently C₁-C₆alkyl, C₁-C₆ alkoxy, halogen, OH, NO₂, C₁-C₂ haloalkyl, C₁-C₂haloalkoxy.

[0108] In another aspect, the invention provides compounds of formulaIV-b, i.e., compounds of formula IV, IV-a, or IV-a-1, wherein R₁ is H,C₁-C₆ alkyl or benzyl (in another aspect, R₁ is H); R₇ isphenyl(C₁-C₄)alkyl, phenyl(C₁-C₆)alkanoyl, benzyloxycarbonyl,benzimidazolylcarbonyl, benzofuranylcarbonyl, thiazolylcarbonyl,indolylcarbonyl, morpholinylcarbonyl, piperazinylcarbonyl,piperidinylcarbonyl, pyrrolidinylcarbonyl, or —SO₂-phenyl wherein thecyclic groups are optionally substituted with 1, 2, 3, or 4 groups thatare independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, NO₂, OH, NH₂,NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, CF₃ or OCF₃.

[0109] In still another aspect, the invention provides compounds offormula IV-c, i.e., compounds of formula IV-b, wherein L₃ is a bond,—CH₂—, or —(C₁-C₂)alkyl-O—; Q is -benzofuranyl-(C₁-C₄)alkyl-phenyl,-pyridyl-(C₁-C₄)alkyl-phenyl, -dibenzofuranyl-(C₁-C₄)alkyl-phenyl,indolyl-(C₁-C₄)alkyl-phenyl, -phenyl-(C₁-C₄)alkyl-benzofuranyl, indolyl,phenyl, benzofuranyl, benzimidazolyl, or dibenzofuranyl, each of whichis optionally substituted with 1, 2, 3, 4, or 5 groups that areindependently C₁-C₆ alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, NH₂, NH(C₁-C₆)alkyl,N(C₁-C₆)alkyl(C₁-C₆)alkyl, or phenyl; and R₂₀, and R₂₁ are independentlyselected from H, benzyloxy, benzyl, halogen, C₁-C₆ alkyl, OH, C₁-C₆alkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, or N(C₁-C₆)alkyl(C₁-C₆)alkyl.

[0110] In still another aspect, the invention provides compounds offormula IV-d, i.e., compounds of formula IV-c, wherein wherein n is 0,1, or 2; L₃ is a bond; R₁ is H; and R₂₀ is H.

[0111] In still another aspect, the invention provides compounds offormula IV-e, i.e., compounds of formula IV-d, wherein R₇ is benzyl,phenyl(C₁-C₆)alkanoyl, benzyloxycarbonyl, benzimidazolylcarbonyl,thiazolylcarbonyl, indolylcarbonyl, morpholinylcarbonyl, or —SO₂-phenylwherein the cyclic groups are optionally substituted with 1, 2, 3, or 4groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, NO₂,OH, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, CF₃ or OCF₃.

[0112] In another aspect, the invention provides compounds of formula V,i.e., compounds and pharmaceutically acceptable salts of formula I thathave the following formula,

[0113] wherein

[0114] n is 0, 1, 2, 3, or 4;

[0115] L₂ is a bond, —O—(C₁-C₆)alkyl-, —(C₁-C₆)alkyl-O—, or—(C₁-C₄)alkyl;

[0116] L₃ is a bond, —(C₁-C₄)alkyl-O—, —O—(C₁-C₄)alkyl, —(C₁-C₄)alkyl-,C₂-C₆ alkenyl, or C(O);

[0117] L₄ is —S(O)_(u)—(C₁-C₄)alkyl-,—(C₁-C₄)alkyl-S(O)_(u)—(C₁-C₄)alkyl-, —(C₁-C₄)alkyl-,—C(O)—(C₁-C₄)alkyl-, —(C₁-C₄)alkyl-C(O)—,—(C₁-C₄)alkyl-C(O)—(C₁-C₄)alkyl-, or —(C₁-C₄)alkyl-NR_(N)—(C₁-C₄)alkyl-where R_(N) represents —(C₁-C₆)alkyl or hydrogen;

[0118] wherein u is 0, 1, or 2;

[0119] R₁ is H, C₁-C₆ alkyl, phenyl(C₁-C₆)alkyl, or C₃-C₆ alkenyl;

[0120] R₆ and R₇ are independently H, C₁-C₆ alkyl, aryl(C₁-C₆)alkyl,(C₂-C₆)alkanoyl, aryl(C₁-C₆)alkanoyl, (C₁-C₆) alkoxycarbonyl,arylalkoxycarbonyl, heteroarylcarbonyl, heteroaryl,heterocycloalkylcarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl,—C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, or —SO₂-aryl, wherein the cyclic groupsare optionally substituted with 1, 2, 3, or 4 groups that areindependently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, NO₂, OH, NH₂,NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, haloalkyl or haloalkoxy;

[0121] each R₁₀ is independently H, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy,C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, orN(C₁-C₆)alkyl(C₁-C₆)alkyl;

[0122] R₂₀, R₂₁, R₂₂, and R₂₃ are independently selected from H,arylalkoxy, arylalkyl, halogen, alkyl, OH, alkoxy, NO₂, NH₂,NH(C₁-C₆)alkyl, or N(C₁-C₆)alkyl(C₁-C₆)alkyl;

[0123] Q is -benzofuranyl-(C₁-C₄)alkyl-phenyl,-pyridyl-(C₁-C₄)alkyl-phenyl, -dibenzofuranyl-(C₁-C₄)alkyl-phenyl,indolyl-(C₁-C₄)alkyl-phenyl, -phenyl-(C₁-C₄)alkyl-benzofuranyl, indolyl,phenyl, indolinyl, benzofuranyl, benzimidazolyl, or dibenzofuranyl, eachof which is optionally substituted with 1, 2, 3, 4, or 5 groups that areindependently C₁-C₆ alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, NH₂, NH(C₁-C₆)alkyl,N(C₁-C₆)alkyl(C₁-C₆)alkyl, or phenyl; and

[0124] Y′ is a bond or —(C₁-C₄)alkyl-.

[0125] In still another aspect, the invention provides compounds offormula V-a, i.e., compounds of formula V, wherein

[0126] R₁ is H, C₁-C₆ alkyl, benzyl, or allyl;

[0127] R₂₃ is H;

[0128] R₆ and R₇ are independently H, C₁-C₆ alkyl, phenyl(C₁-C₆)alkyl,(C₂-C₆)alkanoyl, phenyl(C₁-C₆)alkanoyl, (C₁-C₆) alkoxycarbonyl,benzyloxycarbonyl, benzimidazolylcarbonyl, benzofuranylcarbonyl,thiazolylcarbonyl, indolylcarbonyl, morpholinylcarbonyl,thiomorpholinylcarbonyl, thiomorpholinyl S,S dioxide-carbonyl,piperazinylcarbonyl, piperidinylcarbonyl, pyrrolidinylcarbonyl,—C(O)NH₂, —C(O)NH(C₁-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, or—SO₂-phenyl wherein the cyclic groups are optionally substituted with 1,2, 3, or 4 groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, NO₂, OH, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, C₁-C₂haloalkyl or C₁-C₂ haloalkoxy.

[0129] In still another aspect, the invention provides compounds offormula V-b, i.e., compounds of formula V-a, wherein

[0130] L₂ is a bond, —O—(C₁-C₆)alkyl-, —(C₁-C₆)alkyl-O—,

[0131] L₃ is a bond, —(C₁-C₄)alkyl-O—, —O—(C₁-C₄)alkyl, or—(C₁-C₄)alkyl-; and

[0132] L₄ is —(C₁-C₄)alkyl-, —S(O)_(u)—CH₂—, or—(C₁-C₄)alkyl-S(O)_(u)—CH₂—;

[0133] wherein u is 0, 1, or 2.

[0134] In yet still another aspect, the invention provides compounds offormula V-c, i.e., compounds of formula V-b of the formula

[0135] In still another aspect, the invention provides compounds offormula V-d, i.e., compounds of formula V-c, wherein Q is-benzofuranyl-(C₁-C₄)alkyl-phenyl, -dibenzofuranyl-(C₁-C₄)alkyl-phenyl,indolyl, phenyl, benzofuranyl, benzimidazolyl, or dibenzofuranyl, eachof which is optionally substituted with 1, 2, 3, 4, or 5 groups that areindependently C₁-C₆ alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,CF₃, OCF₃, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, or phenyl.

[0136] In still another aspect, the invention provides compounds offormula V-e, i.e., compounds of formula V-d, wherein R₁ is H, or C₁-C₆alkyl; R₆ is H; at least one of R₂₀ and R₂₁ is H; and L₄ is—(C₁-C₄)alkyl-, —S(O)_(u)—CH₂—, S(O)_(u)—CH₂CH₂—, or —CH₂—S(O)_(u)—CH₂—;wherein u is 0, 1, or 2.

[0137] In yet another aspect, the invention provides compounds offormula V-f, i.e., compounds of formula V-e, wherein R₇ is C₁-C₆ alkyl,(C₂-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl,or —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl.

[0138] In yet another aspect, the invention provides compounds offormula V-g, i.e., compounds of formula V-e, wherein R₇ isphenyl(C₁-C₄)alkyl, phenyl(C₁-C₆)alkanoyl, benzyloxycarbonyl,benzimidazolylcarbonyl, benzofuranylcarbonyl, thiazolylcarbonyl,indolylcarbonyl, morpholinylcarbonyl, piperazinylcarbonyl,piperidinylcarbonyl, pyrrolidinylcarbonyl, or —SO₂-phenyl wherein thecyclic groups are optionally substituted with 1, 2, 3, or 4 groups thatare independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, NO₂, OH, NH₂,NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, CF₃ or OCF₃.

[0139] In yet another aspect, the invention provides compounds offormula V-f, i.e., compounds of formula V-e,

[0140] wherein

[0141] n is 0, 1, or 2; L₃ is a bond, —CH₂—, or —(C₁-C₂)alkyl-O—; and

[0142] each R₁₀ is independently H, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy,CF₃, OCF₃, NO₂, NH₂, NH(C₁-C₆)alkyl, or N(C₁-C₆)alkyl(C₁-C₆)alkyl.

[0143] In yet another aspect, the invention provides compounds offormula V-g, i.e., compounds of formula V-f, wherein Q is-benzofuranyl-(C₁-C₄)alkyl-phenyl, indolyl, phenyl, or dibenzofuranyl,each of which is optionally substituted with 1, 2, 3, 4, or 5 groupsthat are independently C₁-C₆ alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy,halogen, CF₃, OCF₃, NH₂, NH(C₁-C₆)alkyl, or N(C₁-C₆)alkyl(C₁-C₆)alkyl.

[0144] In yet another aspect, the invention provides compounds offormula V-h, i.e., compounds of formula V-g, wherein R₇ is benzyl,phenyl(C₁-C₄)alkanoyl, benzyloxycarbonyl, or —SO₂-phenyl wherein thecyclic groups are optionally substituted with 1, 2, or 3 groups that areindependently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, NO₂, OH, NH₂,NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, CF₃ or OCF₃.

[0145] In still another aspect, the invention provides compounds offormula V-i, i.e., compounds of formula V-h, wherein Q is-benzofuranyl-CH₂-phenyl, indolyl or dibenzofuranyl, each of which isoptionally substituted with 1, 2, 3, 4, or 5 groups that areindependently C₁-C₆ alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,CF₃, OCF₃, NH₂, NH(C₁-C₆)alkyl, or N(C₁-C₆)alkyl(C₁-C₆)alkyl.

[0146] In yet still another aspect, the invention provides compounds offormula V-j, i.e., compounds of formula V-i, wherein n is 0, 1, or 2; L₃is a bond; R₁ is H; and R₂₀ is H.

[0147] In still yet another aspect, the invention provides compounds offormula V-k, i.e., compounds of formula V-i, wherein L₄ is —CH₂—,—CH₂—S—CH₂—, —S—CH₂CH₂—, or —S—CH₂—.

[0148] In another aspect, the invention provides compounds of formulaV-1, i.e., compounds of formula V of the formula

[0149] wherein R₂₀, and R₂₁ are independently selected from H,benzyloxy, benzyl, halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, NO₂, NH₂,NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, NH-phenyl,N(C₁-C₄)alkyl-aryl, —NHSO₂-phenyl, or —N(C₁-C₄ alkyl)SO₂phenyl, whereinthe phenyl group is optionally substituted with 1, 2, 3, or 4 groupsthat are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH, NO₂,C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy.

[0150] In another aspect, the invention provides compounds of formulaV-m, i.e., compounds of formula V-1 wherein R₁ is H, C₁-C₄ alkyl orbenzyl; R₇ is phenyl(C₁-C₄)alkyl, phenyl(C₁-C₆)alkanoyl,benzyloxycarbonyl, benzimidazolylcarbonyl, benzofuranylcarbonyl,thiazolylcarbonyl, indolylcarbonyl, morpholinylcarbonyl,piperazinylcarbonyl, piperidinylcarbonyl, pyrrolidinylcarbonyl, or—SO₂-phenyl wherein the cyclic groups are optionally substituted with 1,2, 3, or 4 groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, NO₂, OH, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, CF₃ orOCF₃.

[0151] In another aspect, the invention provides compounds of formulaV-n, i.e., compounds of formula V-m, wherein L₃ is a bond, —CH₂—, or—(C₁-C₂)alkyl-O—; Q is -benzofuranyl-(C₁-C₄)alkyl-phenyl,-dibenzofuranyl-(C₁-C₄)alkyl-phenyl, indolyl, phenyl, benzofuranyl,benzimidazolyl, or dibenzofuranyl, each of which is optionallysubstituted with 1, 2, 3, 4, or 5 groups that are independently C₁-C₆alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, CF₃, OCF₃, NH₂,NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, or phenyl; each R₁₀ isindependently H, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, OCF₃, NO₂,NH₂, NH(C₁-C₆)alkyl, or N(C₁-C₆)alkyl(C₁-C₆)alkyl; and R₂₀, and R₂₁ areindependently selected from H, benzyloxy, benzyl, halogen, C₁-C₆ alkyl,OH, C₁-C₆ alkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, orN(C₁-C₆)alkyl(C₁-C₆)alkyl.

[0152] In another aspect, the invention provides compounds of formulaV-o, i.e., compounds of formula V-n, wherein n is 0, 1, or 2; L₃ is abond; R₁ is H; and R₂₀ is H.

[0153] In another aspect, the invention provides compounds of formulaV-p, i.e., compounds of formula V-o, wherein R₇ is benzyl,phenyl(C₁-C₆)alkanoyl, benzyloxycarbonyl, C₁-C₄ alkoxycarbonyl,pyridylcarbonyl, benzimidazolylcarbonyl, thiazolylcarbonyl,indolylcarbonyl, morpholinylcarbonyl, or —SO₂-phenyl, wherein eachcyclic groups is optionally substituted with 1, 2, 3, or 4 groups thatare independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, NO₂, OH, NH₂,NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, CF₃ or OCF₃.

[0154] In another aspect, the invention is a method of treating diabetescomprising administering a pharmaceutically acceptable amount of acompound of formula 1 to a patient in need of such treatment.

[0155] In another aspect, the invention is a pharmaceutical compositioncomprising a compound of embodiment 1 and at least one pharmaceuticallyacceptable solvent, carrier, adjuvant or excipient.

[0156] In another aspect, the invention provides a method of treatingdiabetes, comprising administering to a patient in need of suchtreatment a pharmaceutically acceptable amount of a compounds of formulaI.

[0157] In another aspect, the invention encompasses a method of treatingdiabetes comprising administering to a patient in need thereof, apharmaceutically acceptable amount of a compound or salt of formula I ora pharmaceutical composition comprising a compound or salt of formula I.

[0158] In another aspect, the invention encompasses a method ofinhibiting TPT-1B comprising administering to a patient in need thereof,a pharmaceutically acceptable amount of a compound or salt of formula Ior a pharmaceutical composition comprising a compound or salt of formulaI.

[0159] In another aspect, the invention encompasses a method of treatingcancer or neurodegenerative diseases comprising administering to apatient in need thereof, a pharmaceutically acceptable amount of acompound or salt of formula I or a pharmaceutical composition comprisinga compound or salt of formula I.

[0160] Illustrative compounds of the invention include the following,which were named using ChemDraw v. 6.02, which is sold byCambridgesoft.com in Cambridge, Mass., or using Name Pro IUPAC NamingSoftware, version 5.09, available from Advanced Chemical Development,Inc., 90 Adelaide Street West, Toronto, Ontario, M5H 3V9, Canada.N-benzoyl-S-{[4′-(2-benzyl-1- benzofuran-3-yl)biphenyl-4-yl]methyl}-L-cysteine

N-(1H-benzimidazol-5- ylcarbonyl)-S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4- yl]methyl}-L-cysteine

N-(tert-butoxycarbonyl)-3- ({[4′-(1H-indol-1-yl)biphenyl-4-yl]methyl}sulfinyl)-L-alanine

N-(tert-butoxycarbonyl)-S- [(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]-L- cysteine

3-{[4-({[5-(benzyloxy)-1H- indol-1- yl]acetyl}amino)benzyl]sulfonyl}-N-(tert-butoxycarbonyl)-D-alanine

[0161] As noted above, the compounds of the invention bind to andpreferably, inhibit PTP-1B. As a result that are useful in the treatmentof various diseases, including controlling or treating Type 2 diabetes,improving glucose tolerance, and in improving insulin sensitivity inpatients in need thereof. The compounds are also useful in treating orcontrolling other PTP-1B mediated diseases, such as the treatment ofcancer, neurodegenerative diseases and the like.

[0162] The term “alkoxy” represents an alkyl group of indicated numberof carbon atoms attached to the parent molecular moiety through anoxygen bridge. Examples of alkoxy groups include, for example, methoxy,ethoxy, propoxy and isopropoxy.

[0163] As used herein, the term “alkyl” includes those alkyl groups of adesigned number of carbon atoms. Alkyl groups may be straight, orbranched. Examples of “alkyl” include methyl, ethyl, propyl, isopropyl,butyl, iso-, sec- and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl,and the like.

[0164] The term “aryl” refers to an aromatic hydrocarbon ring systemcontaining at least one aromatic ring. The aromatic ring may optionallybe fused or otherwise attached to other aromatic hydrocarbon rings ornon-aromatic hydrocarbon rings. Examples of aryl groups include, forexample, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalene and biphenyl.Preferred examples of aryl groups include phenyl, naphthyl, andanthracenyl. More preferred aryl groups are phenyl and naphthyl. Mostpreferred is phenyl.

[0165] The term “cycloalkyl”, refers to a C₃-C₈ cyclic hydrocarbon.Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl.

[0166] The terms “halogen” or “halo” indicate fluorine, chlorine,bromine, and iodine.

[0167] The term “heterocycloalkyl,” refers to a ring or ring systemcontaining at least one heteroatom selected from nitrogen, oxygen, andsulfur, wherein said heteroatom is in a non-aromatic ring. Theheterocycloalkyl ring is optionally fused to or otherwise attached toother heterocycloalkyl rings and/or non-aromatic hydrocarbon ringsand/or phenyl rings. Preferred heterocycloalkyl groups have from 3 to 7members. Examples of heterocycloalkyl groups include, for example,1,2,3,4-tetrahydroisoquinolinyl, piperazinyl, morpholinyl, piperidinyl,tetrahydrofuranyl, pyrrolidinyl, pyridinonyl, and pyrazolidinyl.Preferred heterocycloalkyl groups include piperidinyl, piperazinyl,morpholinyl, pyrrolidinyl, pyridinonyl, dihydropyrrolidinyl, andpyrrolidinonyl.

[0168] The term “heteroaryl” refers to an aromatic ring systemcontaining at least one heteroatom selected from nitrogen, oxygen, andsulfur. The heteroaryl ring may be fused or otherwise attached to one ormore heteroaryl rings, aromatic or non-aromatic hydrocarbon rings orheterocycloalkyl rings. Examples of heteroaryl groups include, forexample, pyridine, furan, thienyl, 5,6,7,8-tetrahydroisoquinoline andpyrimidine. Preferred examples of heteroaryl groups include thienyl,benzothienyl, pyridyl, quinolyl, pyrazolyl, pyrimidyl, imidazolyl,benzimidazolyl, furanyl, benzofuranyl, dibenzofuranyl, thiazolyl,benzothiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl,triazolyl, pyrrolyl, indolyl, pyrazolyl, and benzopyrazolyl.

[0169] The compounds of this invention may contain one or moreasymmetric carbon atoms, so that the compounds can exist in differentstereoisomeric forms. These compounds can be, for example, racemates,chiral non-racemic or diastereomers. In these situations, the singleenantiomers, i.e., optically active forms, can be obtained by asymmetricsynthesis or by resolution of the racemates. Resolution of the racematescan be accomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent; chromatography,using, for example a chiral HPLC column; or derivatizing the racemicmixture with a resolving reagent to generate diastereomers, separatingthe diastereomers via chromatography, and removing the resolving agentto generate the original compound in enantiomerically enriched form. Anyof the above procedures can be repeated to increase the enantiomericpurity of a compound.

[0170] When the compounds described herein contain olefinic double bondsor other centers of geometric asymmetry, and unless otherwise specified,it is intended that the compounds include the cis, trans, Z- andE-configurations. Likewise, all tautomeric forms are also intended to beincluded.

[0171] The compounds of general Formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes percutaneous, subcutaneous, intravascular (e.g.,intravenous), intramuscular, or intrathecal injection or infusiontechniques and the like. In addition, there is provided a pharmaceuticalformulation comprising a compound of general Formula I and apharmaceutically acceptable carrier. One or more compounds of generalFormula I may be present in association with one or more non-toxicpharmaceutically acceptable carriers and/or diluents and/or adjuvants,and if desired other active ingredients. The pharmaceutical compositionscontaining compounds of general Formula I may be in a form suitable fororal use, for example, as tablets, troches, lozenges, aqueous or oilysuspensions, dispersible powders or granules, emulsion, hard or softcapsules, or syrups or elixirs.

[0172] Compositions intended for oral use may be prepared according toany method known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preservative agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients that are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques. In some cases such coatings may be prepared by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

[0173] Formulations for oral use may also be presented as hard gelatincapsules, wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin or oliveoil.

[0174] Formulations for oral use may also be presented as lozenges.

[0175] Aqueous suspensions contain the active materials in admixturewith excipients suitable for the manufacture of aqueous suspensions.Such excipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

[0176] Oily suspensions may be formulated by suspending the activeingredients in a vegetable oil, for example arachis oil, olive oil,sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.The oily suspensions may contain a thickening agent, for examplebeeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoringagents may be added to provide palatable oral preparations. Thesecompositions may be preserved by the addition of an anti-oxidant such asascorbic acid.

[0177] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Suitable dispersing or wettingagents or suspending agents are exemplified by those already mentionedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present.

[0178] Pharmaceutical compositions of the invention may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oil ora mineral oil or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

[0179] Syrups and elixirs may be formulated with sweetening agents, forexample glycerol, propylene glycol, sorbitol, glucose or sucrose. Suchformulations may also contain a demulcent, a preservative and flavoringand coloring agents. The pharmaceutical compositions may be in the formof a sterile injectable aqueous or oleaginous suspension. Thissuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents that havebeen mentioned above. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxic parentallyacceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

[0180] The compounds of general Formula I may also be administered inthe form of suppositories, e.g., for rectal administration of the drug.These compositions can be prepared by mixing the drug with a suitablenon-irritating excipient that is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials include cocoa butter andpolyethylene glycols.

[0181] Compounds of general Formula I may be administered parenterallyin a sterile medium. The drug, depending on the vehicle andconcentration used, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

[0182] For disorders of the eye or other external tissues, e.g., mouthand skin, the formulations are preferably applied as a topical gel,spray, ointment or cream, or as a suppository, containing the activeingredients in a total amount of, for example, 0.075 to 30% w/w,preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w. Whenformulated in an ointment, the active ingredients may be employed witheither paraffinic or a water-miscible ointment base.

[0183] Alternatively, the active ingredients may be formulated in acream with an oil-in-water cream base. If desired, the aqueous phase ofthe cream base may include, for example at least 30% w/w of a polyhydricalcohol such as propylene glycol, butane-1,3-diol, mannitol, sorbitol,glycerol, polyethylene glycol and mixtures thereof. The topicalformulation may desirably include a compound which enhances absorptionor penetration of the active ingredient through the skin or otheraffected areas. Examples of such dermal penetration enhancers includedimethylsulfoxide and related analogs. The compounds of this inventioncan also be administered by a transdermal device. Preferably topicaladministration will be accomplished using a patch either of thereservoir and porous membrane type or of a solid matrix variety. Ineither case, the active agent is delivered continuously from thereservoir or microcapsules through a membrane into the active agentpermeable adhesive, which is in contact with the skin or mucosa of therecipient. If the active agent is absorbed through the skin, acontrolled and predetermined flow of the active agent is administered tothe recipient. In the case of microcapsules, the encapsulating agent mayalso function as the membrane. The transdermal patch may include thecompound in a suitable solvent system with an adhesive system, such asan acrylic emulsion, and a polyester patch. The oily phase of theemulsions of this invention may be constituted from known ingredients ina known manner. While the phase may comprise merely an emulsifier, itmay comprise a mixture of at least one emulsifier with a fat or an oilor with both a fat and an oil. Preferably, a hydrophilic emulsifier isincluded together with a lipophilic emulsifier which acts as astabilizer. It is also preferred to include both an oil and a fat.Together, the emulsifier(s) with or without stabilizer(s) make-up theso-called emulsifying wax, and the wax together with the oil and fatmake up the so-called emulsifying ointment base which forms the oilydispersed phase of the cream formulations. Emulsifiers and emulsionstabilizers suitable for use in the formulation of the present inventioninclude Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol,glyceryl monostearate, and sodium lauryl sulfate, among others. Thechoice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties, since the solubility of theactive compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

[0184] Formulations suitable for topical administration to the eye alsoinclude eye drops wherein the active ingredients are dissolved orsuspended in suitable carrier, especially an aqueous solvent for theactive ingredients. The antiinflammatory active ingredients arepreferably present in such formulations in a concentration of 0.5 to20%, advantageously 0.5 to 10% and particularly about 1.5% w/w. Fortherapeutic purposes, the active compounds of this combination inventionare ordinarily combined with one or more adjuvants appropriate to theindicated route of administration. If administered per os, the compoundsmay be admixed with lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropylmethyl cellulose.Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules having one or more of the carriers or diluents mentioned foruse in the formulations for oral administration. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, and/or various buffers. Other adjuvants and modes ofadministration are well and widely known in the pharmaceutical art.

[0185] Dosage levels of the order of from about 0.1 mg to about 140 mgper kilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient. The daily dose can be administered in one tofour doses per day. In the case of skin conditions, it may be preferableto apply a topical preparation of compounds of this invention to theaffected area two to four times a day.

[0186] It will be understood, however, that the specific dose level forany particular patient will depend upon a variety of factors includingthe activity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

[0187] For administration to non-human animals, the composition may alsobe added to the animal feed or drinking water. It may be convenient toformulate the animal feed and drinking water compositions so that theanimal takes in a therapeutically appropriate quantity of thecomposition along with its diet. It may also be convenient to presentthe composition as a premix for addition to the feed or drinking water.Preferred non-human animals include domesticated animals.

[0188] As noted above, the invention also provides methods andcompositions for combination therapy of Type I and Type II diabetes. Inone such aspect, the invention provides methods of using compounds offormula I in combination with one or more angiotensin converting enzyme(ACE) inhibitors for improving the cardiovascular risk profile inpatients experiencing or subject to Syndrome X or type II diabetes(non-insulin-dependent diabetes mellitus), preferably in human type IIdiabetics. These methods may also be characterized as the reduction ofrisk factors for heart disease, stroke or heart attack in a type IIdiabetic.

[0189] These methods include the reduction of hyperlipidemia in apatients experiencing or subject to Syndrome X or type II diabetes.These methods include methods lowering low density lipoprotein (LDL)blood levels and to increase high density lipoprotein (HDL) bloodlevels. The methods herein may further be characterized as useful forinhibiting, preventing or reducing atherosclerosis in a type IIdiabetics, or for reducing the risk factors thereof.

[0190] These methods also include the lowering of free fatty acid bloodlevels and triglyceride levels in type II diabetics.

[0191] Among the ACE inhibitors which may be utilized with the inventiondescribed herein are quinapril, ramipril, verapamil, captopril,diltiazem, clonidine, hydrochlorthiazide, benazepril, prazosin,fosinopril, lisinopril, atenolol, enalapril, perindropril, perindropriltert-butylamine, trandolapril and moexipril, or a pharmaceuticallyacceptable salt form of one or more of these compounds.

[0192] The invention also provides methods of using PTPase inhibitors offormula I for improving the cardiovascular or cerebrovascular riskprofile in patients experiencing or subject to type II diabetes(non-insulin-dependent diabetes mellitus), preferably in human type IIdiabetics or a patient experiencing or subject to Syndrome X. Thesemethods may also be characterized as the reduction of risk factors forheart disease, stroke or heart attack in a type II diabetic or a patientexperiencing or subject to Syndrome X.

[0193] The invention also provides methods of using a pharmacologicalcombination of one or more PTPase inhibiting agents, one or morebiguanide agents, and, optionally one or more sulfonlylurea agents fortreatment of type II diabetes or Syndrome X in a patient in need of suchtreatment. Also provided are methodS of using these agents to treat orinhibit metabolic disorders mediated by insulin resistance orhyperglycemia in a patient in need thereof. Further included in thisinvention is a method of modulating blood glucose levels in a patient inneed thereof.

[0194] Each of these methods comprises administering to a patient inneed thereof pharmaceutically effective amounts of:

[0195] a) a PTPase inhibiting agent of formula I; and

[0196] b) a biguanide agent; and

[0197] c) optionally, a sulfonylurea agent.

[0198] Biguanide agents useful with this invention include metformin andits pharmaceutically acceptable salt forms. Sulfonylurea agents usefulfor the methods and combinations of this invention may be selected fromthe group of glyburide, glyburide, glipizide, glimepiride,chlorpropamide, tolbutamide, or tolazamide, or a pharmaceuticallyacceptable salt form of these agents.

[0199] This invention also provides pharmaceutical compositions andmethods of using PTPase inhibitors of formula I in combination with oneor more alpha-glucosidase inhibitors, such as miglitol or acarbose, forimproving the cardiovascular risk profile in patients experiencing orsubject to Syndrome X or type II diabetes (non-insulin-dependentdiabetes mellitus), preferably in human type II diabetics. These methodsmay also be characterized as the reduction of risk factors for heartdisease, stroke or heart attack in a patient in such need.

[0200] These methods include the reduction of hyperlipidemia in type IIdiabetics, including methods in type II diabetics for lowering lowdensity lipoprotein (LDL) blood levels and to increase high densitylipoprotein (HDL) blood levels. The methods herein may further becharacterized as useful for inhibiting, preventing or reducingatherosclerosis in a type II diabetic or a patient experiencing orsubject to Syndrome X, or the risk factors of either.

[0201] These methods also include the lowering free fatty acid bloodlevels and triglyceride levels in type II diabetics, or a patientexperiencing or subject to Syndrome X.

[0202] Among the alpha-glucosidase inhibitors which may be utilized withthe invention described herein are miglitol or acarbose, or apharmaceutically acceptable salt form of one or more of these compounds.

[0203] This invention further provides methods for using a PTPaseinhibitor of the invention and a sulfonylurea agent for the managementof Syndrome X or type 2 diabetes and for improving the cardiovascularrisk profile in patients experiencing or subject to those maladies.These methods may also be characterized as the reduction of risk factorsin such patients for heart disease, stroke or heart attack in a type IIdiabetic. Such methods include the reduction of hyperlipidemia in apatients experiencing or subject to Syndrome X or type II diabetes andinclude methods for lowering low density lipoprotein (LDL) blood levels,high density lipoprotein (HDL) blood levels, and overall bloodlipoprotein levels. The methods herein may further be characterized asinhibiting, preventing or reducing atherosclerosis in patients subjectto or experiencing Syndrome X or type II diabetes, or the risk factorsthereof. Such methods further include the lowering of free fatty acidblood levels and triglyceride levels in such patients.

[0204] Representative sulfonylurea agents include glipizide, glyburide(glibenclamide), chlorpropamide, tolbutamide, tolazamide andglimepriride, or the pharmaceutically acceptable salt forms thereof.

[0205] In addition, the invention provides combinations of a PTPaseinhibitor of the invention and at least one thiazolidinedione agents.Such combinations are useful for treatment, inhibition or maintenance ofSyndrome X or type II diabetes in patients in need of such treatment.Accordingly, methods of using such combinations are provided by theinvention. Thus, the invention provides methods of using these agents totreat or inhibit metabolic disorders mediated by insulin resistance orhyperglycemia in patients in need thereof. Further included in thisinvention are methods of modulating blood glucose levels in a patient inneed thereof.

[0206] Each of these methods comprises administering to a patient inneed thereof pharmaceutically effective amounts of:

[0207] a) a thiazolidinedione agent, such as selected from the group ofpioglitizone and rosiglitazone, or a pharmaceutically acceptable saltform of these agents; and

[0208] b) a compound of formula I.

[0209] The invention also provides pharmaceutical compositions andmethods of using PTPase inhibitors in combination with one or moreantilipemic agents. Such methods and compositions are useful forimproving the cardiovascular risk profile in patients experiencing orsubject to type II diabetes (non-insulin-dependent diabetes mellitus),preferably in type II diabetics or Syndrome X. These methods alsoinclude reducing the risk factors for heart disease, stroke or heartattack in a type II diabetic or a patient experiencing or subject toSyndrome X. Such methods further include the reduction of hyperlipidemiain type II diabetics, including such methods in type II diabetics forlowering low density lipoprotein (LDL) blood levels and to increase highdensity lipoprotein (HDL) blood levels. These compositions and methodsare also useful for inhibiting, preventing or reducing atherosclerosisin a type II diabetic or a patient experiencing or subject to SyndromeX, or the risk factors thereof. In this aspect, the compositions andmethods are useful for lowering of free fatty acid blood levels andtriglyceride levels in type II diabetics, or patients experiencing orsubject to Syndrome X.

[0210] Representative antilipemic or agents, also known asantihyperlipidemic agents, suitable for use in the invention are bileacid sequestrants, fibric acid derivatives, HMG-CoA reductase inhibitorsand nicotinic acid compounds. Bile acid sequestrant agents useful withthis invention include colestipol and colesevelam, and theirpharmaceutically acceptable salt forms. Fibric acid derivatives whichmay be used with the present invention include clifofibrate, gemfibroziland fenofibrate. HMG-CoA reductase inhibitors, also known as statins,useful with this invention include cerivastatin, fluvastatin,atorvastatin, lovastatin, pravastatin and simvastatin, or thepharmaceutically acceptable salt forms thereof. Niacin is an example ofa nicotinic acid compound which may be used with the methods of thisinvention. Also useful are lipase inhibiting agents, such as orlistat.

[0211] This invention also provides pharmaceutical compositions that area combination of a compound of Formula I and an aldose reductaseinhibitor (ARI). Such combinations are useful in methods for treating,inhibiting or preventing type II diabetes, or its related and associatedsymptoms, disorders and maladies. These methods comprise administeringto a patient in need of such therapy a pharmaceutically effective amountof a composition comprising a combination of pharmaceutically effectiveamounts of a compound of formula I and an ARI. These compositions andmethods are useful for the treatment, prevention or inhibition ofdiabetic neuropathy, diabetic nephropathy, retinopathy, keratopathy,diabetic uveitis, cataracts.

[0212] Representative suitable ARIs are disclosed in U.S. Pat. Nos.6,420,426 and 6,214,991.

[0213] Combinations of the compounds of Formula I and an ARI are alsouseful for inhibition or reduction of risk factors for heart disease,stroke or heart attack in a type II diabetic. Therefore, in this aspectthe invention is useful for reducing hyperlipidemia and/or low densitylipoprotein (LDL) blood levels in type II diabetics. Also included inthis aspect are methods for inhibiting, preventing or reducingatherosclerosis or the risk factors thereof in type II diabetics. Thisaspect includes lowering of free fatty acid blood levels andtriglyceride levels.

[0214] This invention also provides methods of using a compound offormula I and insulin(s) for the management of type I or type IIdiabetes. Accordingly, the invention provides for combination therapy,i.e., where a compound of Formula I is administered in combination withinsulin. Such combination therapy encompasses simultaneous or sequentialadministration of the compound of Formula I and insulin. The insulinsuseful in this aspect include both naturally occurring and syntheticinsulins.

[0215] Insulins useful with the methods and combinations of thisinvention include rapid acting insulins, intermediate acting insulins,long acting insulins and combinations of intermediate and rapid actinginsulins.

[0216] Rapid acting commercially available insulin products includeHUMALOG® Brand Lispro Injection (rDNA origin); HUMULIN® Regular HumanInjection, USP [rDNA origin]; HUMULIN® Regular U-500 Concentrated HumanInjection, USP [rDNA origin]; REGULAR ILETIN® II (insulin injection,USP, purified pork) available from Eli Lilly and Co.; and the NOVALIN®Human Insulin Injection and VENOSULIN® BR Buffered Regular HumanInjection, each available from Novo Nordisk Pharmaceuticals.

[0217] Commercially available intermediate acting insulins useful withthis invention include, but are not limited to, the HUMULIN® L brandLENTE® human insulin [rDNA origin] zinc suspension, HUMULIN® N NPH humaninsulin [rDNA origin] isophane suspension, LENTE® ILETIN.RTM. II insulinzinc suspension, USP, purified pork, and NPH ILETIN® II isophane insulinsuspension, USP, purified pork, available from Eli Lilly and Company,LANTUS® insulin glargine [rDNA origin] injection, available from AventisPharmaceuticals, and the NOVOLIN L Lente® human insulin zinc suspension(recombinant DNA origin), and NOVOLIN® N NPH human insulin isophanesuspension (recombinant DNA origin) products available from Novo NordiskPharmaceuticals, Inc, Princeton N.J.

[0218] Also useful with the methods and formulations of this inventionare intermediate and rapid acting insulin combinations, such as theHUMALOG® Mix 75/25 (75% Insulin Lispro Protamine Suspension and 25%Insulin Lispro Injection), HUMULIN® 50/50 (50% Human Insulin IsophaneSuspension and 50% Human Insulin Injection) and HUMULIN® 70/30 (70%Human Insulin Isophane Suspension and 30% Human Insulin Injection), eachavailable from Eli Lilly and Company. Also useful are the NOVALIN® 70/30(70% NPH, Human Insulin Isophane Suspension and 30% Regular, HumanInsulin Injection) line of combination products available from NovoNordisk Pharmaceuticals.

[0219] A commercially available long acting insulin for use with thisinvention is the HUMULIN® U Ultralente® human insulin [rDNA origin]extended zinc suspension, available from Eli Lilly and Company.

[0220] Also useful in the methods of this invention are inhaled insulinproducts, such as the EXUBERA® inhaled insulin product developed byPfizer Inc. and Aventis SA.

[0221] Each of these insulin products can be administered as directed bya medical professional using administrations, dosages and regimens knownin the art, such as those published for each product in the Physicians'Desk Reference, 55 Edition, 2001, published by Medical EconomicsCompany, Inc. at Montvale, N.J., the relevant sections of which areincorporated herein by reference.

[0222] In this aspect, the invention includes, for example, methods forimproving the cardiovascular and cerebrovascular risk profiles inpatients experiencing or subject to type I or type II diabetes(non-insulin-dependent diabetes mellitus), preferably in human type IIdiabetics. These methods may also be characterized as the inhibition orreduction of risk factors for heart disease, stroke or heart attack in atype II diabetic.

[0223] The compounds of the present invention may be prepared by use ofknown chemical reactions and procedures. Representative methods forsynthesizing compounds of the invention are presented below. It isunderstood that the nature of the substituents required for the desiredtarget compound often determines the preferred method of synthesis. Allvariable groups of these methods are as described in the genericdescription if they are not specifically defined below.

[0224] Methods of Preparation

[0225] A method for preparing the compounds of the invention is outlinedin scheme 1. Here, the biphenyl core is coupled to a Q-ring via atransition metal catalyzed reaction. The aldehyde in the resultingcoupled product is reduced and then converted into a leaving group usingmethods known in the art. The leaving group is then displaced via anucleophilic substitution. Depending on the desired final product, theCO₂R₁ group (wherein R₁ is C₁-C₆ alkyl) may be hydrolyzed to form a CO₂Hgroup, and any protecting groups may be removed using methods known inthe art.

[0226] Additionally, if the nucleophile is a thiol (as shown above),then the resulting thioether linkage may be oxidized to the sulfoxide orsulfone using methods known in the art.

[0227] Furthermore, if there is an amine in the molecule, it may beelaborated by methods known in the art to form an amide, or sulfonamide,or the amine may be reacted with an aldehyde and a reducing agent toform an N-alkyl amine.

[0228] Those having skill in the art will recognize that the startingmaterials and reaction conditions may be varied, the sequence of thereactions altered, and additional steps employed to produce compoundsencompassed by the present invention, as demonstrated by the followingexamples. In some cases, protection of certain reactive functionalitiesmay be necessary to achieve some of the above transformations. Ingeneral, the need for such protecting groups as well as the conditionsnecessary to attach and remove such groups will be apparent to thoseskilled in the art of organic synthesis.

[0229] The disclosures of all articles and references mentioned in thisapplication, including patents, are incorporated herein by reference intheir entirety.

[0230] The preparation of the compounds of the present invention isillustrated further by the following examples, which are not to beconstrued as limiting the invention in scope or spirit to the specificprocedures and compounds described in them. In all cases, unlessotherwise specified, the column chromatography is performed using asilica gel solid phase.

EXPERIMENTAL PROCEDURES Example 1

[0231]2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-propionicAcid

[0232] Step 1: Preparation of4′-Dibenzofuran-4-yl-biphenyl-4-carbaldehyde

[0233] A solution of dibenzofuran-4-boronic acid (1.0 g, 4.7 mmol) inethanol (10 mL) was added to a stirred solution of 1-bromo-4-iodobenzene(1.33 g, 4.7 mmol) and tetrakis-(triphenylphosphine)-palladium(0) (271mg, 5 mol %) in toluene (40 mL). 2 N sodium carbonate (4.7 mL, 9.4 mmol)was added and then the reaction was heated to 90° C. (oil bath temp.)for 2-3 h until complete (TLC control). The reaction mixture was cooledto room temperature and partitioned between water and diethyl ether. Thephases were separated, the aqueous phase being further extracted withdiethyl ether (2×20 mL). The combined organic extracts were washed withwater and sat'd aq NaCl. The ethereal solution was dried over anhydMgSO₄, filtered and concentrated in vacuo to yield4-(4-bromophenyl)-dibenzofuran as a yellow solid, which was usedimmediately without further purification.

[0234] A solution of 4-formylphenylboronic acid (0.9 g, 5.64 mmol) inethanol (10 mL) was added to a stirred solution of the crude4-(4-bromophenyl)-dibenzofuran (from the previous reaction) in toluene(40 mL). Tetrakis-(Triphenylphosphine)-palladium(0) (270 mg, 5 mol %)and 2 N sodium carbonate (4.7 mL, 9.4 mmol) were added and then thereaction was heated to 100° C. (oil bath temp.) for 2-3 h until complete(TLC control). The reaction mixture was cooled to room temperature andpartitioned between water and ethyl acetate. The phases were separated,the aqueous phase being further extracted with ethyl acetate (2×20 mL).The combined organic extracts were washed with 0.5 N hydrochloric acid,water and sat'd aq NaCl and then dried over anhyd MgSO₄, filtered andconcentrated in vacuo. Purification by flash column chromatography(10-20% ethyl acetate in heptane) afforded the title compound has awhite solid (1.51 g).

[0235] Step 2: Preparation of (4′-Dibenzofran-4-yl-bipenyl-4-yl)methanol

[0236] Sodium borohydride (322 mg, 8.4 mmol) was added portion-wise to astirred solution of aldehyde (prepared in the previous step) (1.48 g,4.2 mmol) in a mixture of anhyd THF and ethanol (1:2, 50 mL) at roomtemperature. The reaction mixture was stirred for 5-10 min at roomtemperature (TLC control), poured into water (50 mL) and acidified to pH4 with 2 N hydrochloric acid, and then extracted with diethyl ether(3×30 mL). The combined organic extracts were washed with 0.5 Nhydrochloric acid (2×10 mL), water and finally sat'd aq NaCl. Theethereal solution was dried over anhyd MgSO₄, filtered and concentratedin vacuo. Purification by flash column chromatography (30% ethyl acetatein heptane) afforded the title compound has a white solid (1.40 g).

[0237] Step 3: Preparation of Methanesulfonic acid,4′-dibenzofuran-4-yl-biphenyl-4-ylmethyl Ester

[0238] Methanesulfonyl chloride (490 mg, 330 μL, 4.3 mmol) was addeddropwise to a cooled (0° C.) solution of alcohol (prepared in theprevious step) (1.38 g, 3.9 mmol) and triethylamine (800 mg, 1.1 mL, 7.9mmol) in anhyd methylene chloride (50 mL). The clear reaction mixturewas stirred at 0° C. for 2-4 h (TLC control), then poured into water (50mL), and extracted with diethyl ether (3×30 mL). The combined extractwas washed with 0.5 N hydrochloric acid (2×10 mL), water and finallysat'd aq NaCl. The ethereal solution was dried over anhyd MgSO₄,filtered and concentrated in vacuo. The crude mesylate was used in thesubsequent alkylation step without further purification.

[0239] Step 4: Preparation of(R)-Methyl-2-tert-butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-propionate.

[0240]L-N-(tert)Butoxycarbonyl cysteine methyl ester (940 mg, 4.0 mmol)was added dropwise to a stirred suspension of mesylate (prepared in theprevious step) (1.65 g, 3.8 mmol) and cesium carbonate (2.6 g, 8.0mmol), in anhyd DMF (50 mL) at room temperature. The reaction mixturewas stirred at room temperature for 2-3 h (TLC control) and then pouredinto water (50 mL) and extracted with diethyl ether (3×50 mL). Thecombined organic extracts were washed with water (2×30 mL), sat'd aqNaCl (3×30 mL), dried over anhyd MgSO₄, filtered and concentrated invacuo. Purification by flash column chromatography (20-40% ethyl acetatein heptane) afforded the title compound has a pale yellow solid (1.96g).

[0241] Step 5: Preparation of(R)-2-tert-Butoxycarbonyl-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-propionicAcid.

[0242] 2 N Sodium hydroxide solution (1.32 mL, 2.64 mmol) was addeddropwise to a stirred solution ofmethyl-2-tert-butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)propionate(500 mg, 0.88 mmol) in tetrahydrofuran (15 mL) and methanol (3 mL). Theclear reaction mixture was stirred at room temperature until thereaction was complete (TLC control), and then diluted with water (10mL), and acidified to pH 3 with 2 N hydrochloric acid. The reactionmixture was extracted with ethyl acetate (2×20 mL). The combined organicextracts were washed with water, sat'd aq NaCl, dried over anhyd MgSO₄,filtered and concentrated in vacuo. Purification by flash columnchromatography (5-10% methanol in methylene chloride) afforded the titlecompound has a white solid (420 mg), mp 205-206° C.

Example 2 Preparation of3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-2-(2-fluoro-5-trifluoromethyl-benzoylamino)-propionicAcid

[0243]

[0244] Step 1: Preparation ofMethyl-2-amino-3-(4′-dibenzofuran-4-ylbipheny-4-ylmethylsulfanyl)-propionate.

[0245] TMS-I (290 mg, 0.21 mL, 1.45 mmol) was added dropwise to astirred solution ofmethyl-2-tert-butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethyl-sulfanyl)-propionate(748 mg, 1.32 mmol) in anhyd methylene chloride (20 mL). The reactionmixture was stirred at room temperature for 20-30 min (TLC control), andthen diluted with water (20 mL). Sat'd aq sodium bicarbonate solutionwas added to adjust the solution to pH 8-9. The reaction mixture wasextracted with diethyl ether (2×30 mL). The combined organic extractswere washed with water, sat'd aq NaCl, dried over anhydrous MgSO₄,filtered and concentrated in vacuo. Purification by flash columnchromatography (5% methanol in methylene chloride) afforded the titlecompound has a pale yellow solid (596 mg).

[0246] Step 2: Preparation ofMethyl-3-(4′-dibenzofuran-4-yl-biphen-4ylmethylsulfanyl)-2(2-fluoro-5-trifluoromethylbenzoylamino)-propionate.

[0247] 2-Fluoro-5-trifluoromethylbenzoic acid (49 mg, 0.24 mmol) wasadded to a stirred solution ofmethyl-2-amino-3-(4′-dibenzofuran-4-ylbipheny-4-ylmethylsulfanyl)-propionate(92 mg, 0.2 mmol), EDCI (58 mg, 0.3 mmol) and triethylamine (404 mg,0.56 mL, 0.4 mmol) in anhyd methylene chloride (5 mL). The reactionmixture was stirred at room temperature for 4-6 h (TLC control) and thendiluted with water (10 mL). The reaction mixture was extracted withethyl acetate (2×20 mL). The combined organic extract were washed withwater, sat'd aq NaCl, dried over anhydrous MgSO₄, filtered andconcentrated in vacuo. Purification by flash column chromatography (30%ethyl acetate in heptane) afforded the title compound has a white solid(117 mg).

[0248] Step 3: Preparation of3-(4′-Dibenzofuran-4-yl-biphen-4ylmethylsulfanyl)-2(2-fluoro-5-trifluoromethyl-benzoylamino)propionicAcid

[0249] 2 N Sodium hydroxide solution (0.25 mL, 0.5 mmol) was addeddropwise to a stirred solution ofmethyl-3-(4′-dibenzofuran-4-yl-biphen-4ylmethylsulfanyl)-2(2-fluoro-5-trifluoromethylbenzoylamino)-propionate(110 mg, 0.17 mmol) in tetrahydrofuran (5 mL) and methanol (1 mL). Theclear reaction mixture was stirred at room temperature until thereaction was complete (TLC control), and then diluted with water (5 mL),and acidified to pH 3 with 2 N hydrochloric acid. The reaction mixturewas extracted with ethyl acetate (2×10 mL). The combined extract waswashed with water, sat'd aq NaCl, dried over anhydrous MgSO₄, filteredand concentrated in vacuo. Purification by flash column chromatography(5-10% methanol in methylene chloride) afforded the title compound has awhite solid (98 mg).

Example 3

[0250] (4′-Indol-1-yl-biphen-4-yl)methanol.

[0251] Sodium borohydride (783 mg, 20.6 mmol) was added portion-wise toa stirred solution of aldehyde (3.06 g, 10.3 mmol) in a mixture ofanhydrous THF and ethanol (1:1; 100 mL) at room temperature. Thereaction mixture was stirred for 10 minutes at room temperature (TLCcontrol), poured into water (50 mL) and acidified to pH 4 with 2Nhydrochloric acid, and then extracted with diethyl ether (3×20 mL). Thecombined extract was washed with 0.5 N hydrochloric acid (2×10 mL),water and finally brine. The ethereal solution was dried over anhydrousMgSO₄, filtered and concentrated in vacuo. Purification of the productby flash column chromatography, using 30% ethyl acetate/hexane aseluent, afforded the title compound has a white solid (2.80 g, 91%); ¹HNMR (CDCl₃, 300 MHz) δ 7.55-7.78 (7H, m, Ar—H), 7.52 (2H, d, J=8 Hz,Ar—H), 7.41 (1H, d, J=3.5 Hz, Ar—H), 7.22 (3H, m, Ar—H), 6.72 (1H, d,J=3.5 Hz, Ar—H), 4.79 (2H, d, J=5.5 Hz, CH₂O).

Example 4

[0252] Methanesulfonic acid, (4′-Indol-1-yl-biphen-4-yl)methyl Ester.

[0253] Methanesulfonyl chloride (194 mg, 131 μL, 1.7 mmol) was addeddropwise to a cooled (0° C.) solution of alcohol (prepared in theprevious step) (620 mg, 1.54 mmol) and triethylamine (311 mg, 0.43 mL,3.08 mmol) in anhydrous methylene chloride (10 mL). The clear reactionmixture was stirred at 0° C. for 2-4 hrs (TLC control), then poured intowater (50 mL), and extracted with diethyl ether (3×30 mL). The combinedextract was washed with 0.5 N hydrochloric acid (2×10 mL), water andfinally brine. The ethereal solution was dried over anhydrous MgSO₄,filtered and concentrated in vacuo. The crude mesylate was used in thesubsequent alkylation step without further purification.

Example 5

[0254](2R)-Methyl-tert-butoxycarbonylamino-3-(4′-indol-1-ylbiphen-4-ylmethylsulfanyl)-propionate.

[0255]L-N-tert-Butoxycarbonyl cysteine methyl ester (3.0 g, 2.6 mL,12.43 mmol) was added dropwise to a stirred suspension of mesylate(prepared according to the method in the previous step) (4.8 g, 12.43mmol) and cesium carbonate (8.3 g, 25 mmol), in anhydrous DMF (100 mL)at room temperature. The reaction mixture was stirred at roomtemperature for 2-3 hrs (TLC control) and then poured into water (50 mL)and extracted with diethyl ether (3×100 mL). The combined extract waswashed with water (2×30 mL), brine (3×30 mL), dried over anhydrousMgSO₄, filtered and concentrated in vacuo. Purification of the productby flash column chromatography, using 30% ethyl acetate/hexane aseluent, afforded the title compound has a white solid (4.68 g, 75%). ¹HNMR (CDCl₃, 300 MHz): δ 7.69-7.82 (3H, m, Ar—H), 7.58 (5H, m, Ar—H),7.42 (2H, d, J=8 Hz, , Ar—H), 7.38 (1H, d, J=3.5 Hz, Ar—H), 7.22 (2H, m,Ar—H), 6.72 (1H, d, J=3.5 Hz, Ar—H), 5.34 (1H, d, J=8 Hz, NH), 4.59 (1H,m, CHN), 3.80 (2H, s, PhCH2), 3.76 (3H, s, OMe), 2.97 (1H, dd, J=13, 5Hz, CHHCHN), 2.86 (1H, dd, J=13, 5 Hz, CHHCHN), 1.47 (9H, s, CMe₃)

Example 6

[0256](2R)-tert-Butoxycarbonylamino-3-(4′-indol-1-ylbiphen-4-ylmethylsulfanyl)-propionicAcid.

[0257] 1N Sodium hydroxide solution (2.14 mL, 2.14 mmol) was addeddropwise to a stirred solution of(2R)-Methyl-tert-butoxycarbonylamino-3-(4′-indol-1-ylbiphen-4-ylmethylsulfanyl)-propionate(552 mg, 1.07 mmol) in tetrahydrofuran (15 mL) and methanol (3 mL). Theclear reaction mixture was stirred at room temperature until thereaction was complete (TLC control), and then diluted with water (10mL), and acidified to pH 3 with 2N hydrochloric acid. The reactionmixture was extracted with ethyl acetate (2×20 mL). The combined extractwas washed with water, brine, dried over anhydrous MgSO₄, filtered andconcentrated in vacuo. Purification of the product by flash columnchromatography, using 5-10% methanol in methylene chloride as eluent,afforded the title compound has a white solid (486 mg, 90%), m.pt.171-173° C. Rf: 0.35 (10% methanol in dichloromethane); ¹H NMR (DMSO-d6,300 MHz): δ 7.86 (2H, d, J=8 Hz, Ar—H), 7.68 (6H, m, Ar—H), 7.61 (1H, d,J=8 Hz, Ar—H), 7.43 (2H, d, J=8 Hz, Ar—H), 7.11-7.22 (2H, m, Ar—H), 6.80(1H, br s, NH), 6.72 (1H, d, J=3.5 Hz, Ar—H), 4.06 (1H, m, CHN), 3.80(2H, s, PhCH2), 2.86 (1H, dd, J=13, 5 Hz, CHHCHN), 2.72 (1H, dd, J=13, 8Hz, CHHCHN), 1.40 (9H, s, CMe₃), ESI-LCMS e/z calcd for C₂₉H₃₀N₂O₄S:502.632, found 503 (M+H)⁺, 525 (M+Na)⁺.

Example 7

[0258](2R)-tert-Butoxycarbonylamino-3-(4′-indol-1-ylbiphen-4-ylmethylsulfinyl)-propionicAcid.

[0259] Sodium perborate tetrahydrate (151 mg, 0.95 mmol) was added as asolid to a stirred solution of(2R)-tert-Butoxycarbonylamino-3-(4′-indol-1-ylbiphen-4-ylmethylsulfanyl)-propionicacid (380 mg, 0.76 mmol) in acetic acid (10 mL) at 40° C. This solutionwas stirred at 40° C. for 2 hours (HPLC control) and then diluted withethyl acetate (50 mL), washed with water, brine (2×), dried overanhydrous MgSO₄, filtered and concentrated in vacuo. Purification bytrituration of the product with diethyl ether afforded the titlecompound as a 2:1 mix of diastereoisomers as an off-white solid (372 mg,95%): mp. 169-170° C. Rf 0.65 (20% methanol in dichloromethane). ¹H NMR(DMSO-d6, 300 MHz): δ 7.88 (2H, d, J=8 Hz, Ar—H), 7.62-7.78 (7H, m,Ar—H), 7.44 (2H, d, J=8 Hz, Ar—H), 7.36 (1H, d, J=8 Hz, NH), 7.11-7.22(2H, m, Ar—H), 6.72 (1H, d, J=3.5 Hz, Ar—H), 4.06-4.26 (3H, m,CHN+PhCH₂), 2.96-3.04 (2H, m, CH ₂CHN), 1.39 (3H, s, CMe₃, minorisomer), 1.36 (6H, s, CMe₃, major isomer), ESI-LCMS e/z calcd forC₂₉H₃₀N₂O₅S: 518.631, found 519 (M+H)⁺, 541 (M+Na)⁺.

Example 8

[0260](2R)-Methyl-2-amino-3-[4′indol-1-yl-biphen-4-ylmethylsulfanyl]propionate.

[0261] TMSI (1.56 mL, 10.63 mmol) was added dropwise to a stirredsolution of(2R)-methyl-tert-butoxycarbonylamino-3-(4′-indol-1-ylbiphen-4-ylmethylsulfanyl)-propionate(4.47 g, 8.66 mmol) in anhydrous methylene chloride (50 mL). Thereaction was stirred for 10 mins. and then poured into 1N sodiumbicarbonate solution (50 mL), extracted with ethyl acetate (3×50 mL).The combined extract was washed with water, brine, dried over anhydrousMgSO₄, filtered and concentrated in vacuo. Purification of the productby flash column chromatography, using 5% methanol in methylene chlorideas eluent, afforded the title compound as a yellow oil (3.43 g, 95%):.Rf=0.65 (10% methanol in dichloromethane). ¹H NMR (DMSO-d6, 300 MHz): δ7.86 (2H, d, J=8 Hz, Ar—H), 7.64-7.72 (6H, m, Ar—H), 7.61 (1H, d, J=8Hz, , Ar—H), 7.42 (1H, d, J=8 Hz, Ar—H), 7.21 (1H, td, J=7, 2 Hz, Ar—H),7.14 (1H, td, J=7, 2 Hz, Ar—H), 6.72 (1H, d, J=3.5 Hz, Ar—H), 3.80 (2H,s, PhCH₂), 3.62 (3H, s, OMe), 3.56 (1H, t, J=6.5 Hz, CHN), 2.68 (1H, dd,J=6.5, 3 Hz, CHHCHN), 2.63 (1H, dd, J=6.5, 3 Hz, CHHCHN), 2.04 (2H, brs, NH₂).

Example 9

[0262] General Methods for the Synthesis 2-N-amido Acids (N-AcylationPlus Subsequent Ester Hydrolysis)

[0263] Method A:

[0264] To a solution of(2R)-methyl-2-amino-3-[4′indol-1-yl-biphen-4-ylmethylsulfanyl]-propionate(0.3 mmol) in a mixture of methylene chloride (5 mL) anddimethylformamide (1 mL) was added the required carboxylic acid (0.37mmol), EDCI (85 mg, 0.43 mmol), HOBt (5 mg) and triethylamine (82 μL).The reaction mixture was stirred for 16 hours and then diluted withdiethyl ether (25 mL), washed with water, brine (2×), dried overanhydrous MgSO₄, filtered and concentrated in vacuo to yield the crudeamido-methyl ester compound.

[0265] 2N Sodium hydroxide (0.5 mL) was added to a stirred solution ofthe amido methyl ester in a mixture of tetrahydrofuran (5 mL) andmethanol (1 mL). The solution was stirred for 1 hour and then acidifiedto pH 3 with 2N hydrochloric acid. The reaction mixture was extractedwith ethyl acetate (3×10 mL). The combined extract was washed withwater, brine, dried over anhydrous MgSO₄, filtered and concentrated invacuo. Purification of the product by flash column chromatography, using5-20% methanol in methylene chloride as eluent, afforded the titlecompound.

[0266] Method B:

[0267] To a solution of(2R)-Methyl-2-Amino-3-[4′indol-1-yl-biphen-4-ylmethylsulfanyl]-propionate(0.3 mmol) in a 1,2-dichloroethane was added the required acid chloride,sulfonyl chloride, carbamoyl chloride or isocyanate (0.37 mmol). Thereaction mixture was stirred for 4 hours and then diluted with diethylether (25 mL), washed with water, brine (2×), dried over anhydrousMgSO₄, filtered and concentrated in vacuo to yield the crudeamido-methyl ester compounds.

[0268] 2N Sodium hydroxide (0.5 mL) was added to a stirred solution ofthe amido methyl ester in a mixture of tetrahydrofuran (5 mL) andmethanol (1 mL). The solution was stirred for 1 hour and then acidifiedto pH 3 with 2N hydrochloric acid. The reaction mixture was extractedwith ethyl acetate (3×10 mL). The combined extract was washed withwater, brine, dried over anhydrous MgSO₄, filtered and concentrated invacuo. Purification of the product by flash column chromatography, using5-20% methanol in methylene chloride as eluent, afforded the titlecompounds.

Example 10

[0269](2R)-3-(4′-Indol-1-ylbiphen-4-ylmethylsulfanyl)-2-[2-(3-nitrophenyl)acetylamino]-propionicAcid

[0270](2R)-3-(4′-Indol-1-ylbiphen-4-ylmethylsulfanyl)-2-[2-(3-nitrophenyl)acetylamino]-propionicacid was prepared according to the method described in Example 9, MethodA, using 3-nitrophenylacetic acid as the corresponding carboxylic acid.

[0271] The title compound was isolated as a pale yellow solid: mp. 94°C. Rf=0.18 (10% methanol in dichloromethane). ¹H NMR (DMSO-d6, 300 MHz)δ 8.46 (1H, d, J=8 Hz, NH), 8.21 (1H, t, J=2 Hz, Ar—H), 8.16 (1H, ddd,J=8, 2, 1 Hz, Ar—H), 7.84 (2H, d, J=8 Hz, Ar—H), 7.76 (1H, d, J=8 Hz,Ar—H), 7.58-7.69 (6H, m, Ar—H), 7.35 (2H, d, J=8 Hz, Ar—H), 7.21 (1H,td, J=7, 2 Hz, Ar—H), 7.14 (1H, td, J=7, 2 Hz, Ar—H), 6.72 (1H, dd, J=3,1 Hz, Ar—H), 4.38 (1H, m, CHN), 3.72 (4H, m, PhCH ₂CO+PhCH ₂S), 2.89(1H, dd, J=13, 5 Hz, CHHCHN, 2.71 (1H, dd, J=13, 8 Hz, CHHCHN); ESI-LCMSe/z calcd for C₃₂H₂₇N₃O₅S 565.647, found 566 (M+H)⁺, 588 (M+Na)⁺.

Example 11

[0272](2R)-3-(4′-Indol-1-ylbiphen-4-ylmethylsulfanyl)-2-phenylacetylamino-propionicAcid

[0273](2R)-3-(4′-Indol-1-ylbiphen-4-ylmethylsulfanyl)-2-phenylacetylamino-propionicacid was prepared according to the method described in Example 9, MethodA, using phenylacetic acid as the corresponding carboxylic acid. Thetitle compound was isolated as a pale pink solid: Rf=0.20 (10% methanolin dichloromethane). ¹H NMR (DMSO-d6, 300 MHz) δ 8.40 (1H, d, J=8 Hz,NH), 7.86 (2H, d, J=8 Hz, Ar—H), 7.60-7.69 (7H, m, Ar—H), 7.38 (2H, d,J=8 Hz, Ar—H), 7.28 (4H, m, Ar—H), 7.12-7.25 (3H, m, Ar—H), 6.72 (1H,dd, J=3, 1 Hz, Ar—H), 4.41 (1H, m, CHN), 3.76 (2H, s, PhCH ₂CO) 3.50(2H, s, PhCH ₂S), 2.86 (1H, dd, J=13, 5 Hz, CHHCHN, 2.73 (1H, dd, J=13,8 Hz, CHHCHN); ESI-LCMS e/z calcd for C₃₂H₂₈N₂O₃S 520.650, found 521(M+H)⁺, 543 (M+Na)⁺.

Example 12

[0274](2R)-3-(4′-Indol-1-ylbiphen-4-ylmethylsulfanyl)-2-methoxycarbonylamino-propionicAcid.

[0275](2R)-3-(4′-Indol-1-ylbiphen-4-ylmethylsulfanyl)-2-methoxycarbonylamino-propionicacid was prepared according to the method described in Example 9, MethodB, using methyl chloro-formate as the corresponding acylating reagent.The title compound was isolated as a cream solid: mp. 81-82° C. Rf=0.45(20% methanol in dichloromethane); ¹H NMR (CDCl₃, 300 MHz): δ 7.58 (3H,m, Ar—H), 7.46 (5H, m, Ar—H), 7.26 (3H, m, Ar—H), 7.10 (2H, m, Ar—H),6.72 (1H, s, Ar—H), 5.52 (1H, br s, NH), 4.32 (1H, m, CHN), 3.70 (2H, s,PhCH₂), 3.58 (3H, s, OMe) 2.88 (2H, s, CH ₂CHN); ESI-LCMS e/z calcd forC₂₆H₂₄N₂O₄S: 460.552, found 461 (M+H)⁺.

Example 13

[0276](2R)-3-(4′-Indol-1-ylbiphen-4-ylmethylsulfanyl)-2-isobutoxycarbonylamino-propionicAcid.

[0277](2R)-3-(4′-Indol-1-ylbiphen-4-ylmethylsulfanyl)-2-isobutoxycarbonylamino-propionicacid was prepared according to the method described in Example 9, MethodB, using isobutyl chloro-formate as the corresponding acylating reagent.The title compound was isolated as a beige solid: mp. 85-86° C. Rf=0.50(20% methanol in dichloromethane); ¹H NMR (CDCl₃, 300 MHz): δ 7.56 (3H,m, Ar—H), 7.52 (5H, m, Ar—H), 7.36 (3H, m, Ar—H), 7.17 (2H, m, Ar—H),6.67 (1H, s, Ar—H), 5.62 (1H, br s, NH), 4.58 (1H, m, CHN), 3.86 (2H, m,OCH₂), 3.78 (2H, s, PhCH₂), 2.98 (2H, s, CH ₂CHN)1.92 (1H, m, CHMe₂),0.91 (6H, d, J=6.5 Hz, CHMe ₂); ESI-LCMS e/z calcd for C₂₉H₃₀N₂O₄S:502.632, found 503 (M+H)⁺.

Example 14

[0278](2R)-3-(4′-Indol-1-ylbiphen-4-ylmethylsulfanyl)-2-[(morpholine-4-carbonyl)-amino]-propionicacid.

[0279](2R)-3-(4′-Indol-1-ylbiphen-4-ylmethylsulfanyl)-2-[(morpholine-4-carbonyl)-amino]-propionicacid was prepared according to the method described in Example 9, MethodB, using 4-morpholinylcarbonyl chloride as the corresponding acylatingreagent. The title compound was isolated as a beige solid: mp. 195° C.(dec.): Rf=0.30 (20% methanol in dichloromethane); ¹H NMR (DMSO-d6, 300MHz): δ 7.82 (3H, d, J=8 Hz, Ar—H), 7.60-7.69 (7H, m, Ar—H, NH), 7.42(2H, d, J=8 Hz, Ar—H), 7.19 (1H, td, J=7, 2 Hz, Ar—H), 7.12 (1H, td,J=7, 2 Hz, Ar—H), 6.71 (1H, d, J=3 Hz, Ar—H), 4.00 (1H, m, CHN), 3.76(2H, d, J=3.5 Hz, PhCH ₂S), 3.56 (4H, m, CH₂OCH₂), 3.26 (4H, m,CH₂NCH₂), 2.91 (1H, dd, J=13, 5 Hz, CHHCHN); 2.79 (1H, dd, J=13, 8 Hz,CHHCHN); ESI-LCMS e/z calcd for C₂₉H₂₉N₃O₄S 515.631, found 516 (M+H)⁺.

Example 15

[0280](2R)-2-(3,3-Dimethylureido)-3-(4′-indol-1-ylbiphen-4-ylmethylsulfanyl)-propionicAcid.

[0281](2R)-2-(3,3-Dimethylureido)-3-(4′-indol-1-ylbiphen-4-ylmethylsulfanyl)-propionicacid was prepared according to the method described in Example 9, MethodB, using N,N-dimethyl-carbamoyl chloride as the corresponding acylatingreagent. The title compound was isolated as a beige solid: mp: Rf=0.40(15% methanol in dichloromethane); ¹H NMR (CDCl₃, 300 MHz): δ 7.66 (2H,m, Ar—H), 7.48-7.62 (6H, m, Ar—H), 7.36 (3H, m, Ar—H), 7.17 (2H, m,Ar—H), 6.68 (1H, s, Ar—H), 5.42 (1H, br s, NH), 4.50 (1H, m, CHN), 3.80(2H, s, PhCH₂), 3.05 (2H, s, CH ₂CHN), 2.89 (6H, s, NMe₂); ESI-LCMS e/zcalcd for C₂₇H₂₇N₃O₃S: 473.594, found 475 (M+H)⁺.

Example 16

[0282](2R)-2-Benzyloxycarbonylamino-3-(4′-Indol-1-ylbiphen-4-ylmethylsulfanyl-propionicAcid.

[0283](2R)-2-Benzyloxycarbonylamino-3-(4′-Indol-1-ylbiphen-4-ylmethylsulfanyl-propionicacid was prepared according to the method described in Example 9, MethodB, using benzylchloroformate as the corresponding acylating reagent. Thetitle compound was isolated as a pale pink solid: Rf=0.50 (15% methanolin dichloromethane); ¹H NMR (CDCl₃, 300 MHz): δ 7.70 (2H, d, J=8 Hz,Ar—H), 7.48-7.62 (6H, m, Ar—H), 7.17-7.36 (10H, m, Ar—H), 6.67 (1H, d,J=3 Hz, Ar—H), 5.80 (1H, br s, NH), 5.16 (2H, m, PhCH ₂O), 4.60 (1H, m,CHN), 3.76 (2H, s, PhCH₂), 2.95 (2H, s, CH ₂CHN); ESI-LCMS e/z calcd forC₃₂H₂₈N₂O₄S: 536.649, found 537 (M+H)⁺.

Example 17

[0284](2R)-3-(4′-Indol-1-ylbiphen-4-ylmethylsulfinyl)-2-[2-(3-nitrophenyl)acetylamino]-propionicAcid.

[0285] Sodium perborate tetrahydrate (97 mg, 0.63 mmol) was added as asolid to a stirred solution of(2R)-3-(4′-Indol-1-ylbiphen-4-ylmethylsulfanyl)-2-[2-(3-nitrophenyl)-acetylamino]-propionicacid (330 mg, 0.58 mmol) in acetic acid (10 mL) at 40° C. This solutionwas stirred at 40° C. for 2 hours (HPLC control) and then diluted withethyl acetate (50 mL), washed with water, brine (2×), dried overanhydrous MgSO₄, filtered and concentrated in vacuo. Purification bytrituration of the product with diethyl ether afforded the titlecompound as a light brown solid (206 mg, 61%): mp. 197-198° C. Rf 0.15(15% methanol in dichloromethane): ¹H NMR (DMSO-d6, 300 MHz) δ 8.46 (1H,d, J=8 Hz, NH), 8.18 (1H, t, J=2 Hz, Ar—H), 8.08 (1H, ddd, J=8, 2, 1 Hz,Ar—H), 7.87 (2H, d, J=8 Hz, Ar—H), 7.72 (2H, d, J=8 Hz, Ar—H), 7.54-7.69(7H, m, Ar—H), 7.35 (2H, d, J=8 Hz, Ar—H), 7.21 (1H, td, J=7, 2 Hz,Ar—H), 7.14 (1H, td, J=7, 2 Hz, Ar—H), 6.71 (1H, d, J=3 Hz, Ar—H), 4.36(1H, m, CHN), 4.20 (1H, d, J=13 Hz, PhCHHS), 3.84 (1H, d, J=13 Hz,PhCHHS), 3.66 (2H, m, PhCH ₂CO), 3.11 (1H, dd, J=13, 5 Hz, CHHCHN), 2.99(1H, dd, J=13, 8 Hz, CHHCHN); ESI-LCMS e/z calcd for C₃₂H₂₇N₃O₆S581.646, found 582 (M+H)⁺, 604 (M+Na)⁺.

Example 18

[0286](2R)-3-(4′-Indol-1-ylbiphen-4-ylmethylsulfinyl)-2-phenylacetylamino-propionicAcid.

[0287] Sodium perborate tetrahydrate (97 mg, 0.63 mmol) was added as asolid to a stirred solution of(2R)-3-(4′-indol-1-ylbiphen-4-ylmethylsulfanyl)-2-phenylacetylamino-propionicacid (300 mg, 0.58 mmol) in acetic acid (10 mL) at 40° C. This solutionwas stirred at 40° C. for 2 hours (HPLC control) and then diluted withethyl acetate (50 mL), washed with water, brine (2×), dried overanhydrous MgSO₄, filtered and concentrated in vacuo. Purification of theproduct by flash column chromatography, using 15% methanol indichloromethane as eluent, afforded the title compound has an off-whitesolid (261 mg g, 84%) as a 1:1 mixture of diasereomers; ¹H NMR (DMSO-d6,300 MHz) δ 12.98 (1H, s, COOH), 8.75 and 8.80 (both 0.5H, d, J=8 Hz,NH), 8.40 (1H, d, J=8 Hz, NH), 7.84 (2H, m, Ar—H), 7.60-7.78 (7H, m,Ar—H), 7.44 and 7.39 (both 1H, d, J=8 Hz, Ar—H), 7.12-7.28 (7H, m,Ar—H), 6.72 (1H, d, J=3 Hz, Ar—H), 4.68 and 4.48 (both 0.5H, m, CHN),4.16 (2H, m, PhCH ₂CO) 3.52 and 3.32 (both 1H, s, PhCH ₂S), 3.09 (1H, m,CHHCHN), 2.96 (1H, m, CHHCHN); ESI-LCMS e/z calcd for C₃₂H₂₈N₂O₄S536.649, found 537 (M+H)⁺.

Example 19

[0288] 4′-Dibenzofuran-4-yl-biphenyl-4-carbaldehyde

[0289] A solution of dibenzofuran-4-boronic acid (1.0 g, 4.7 mmol) inethanol (10 mL) was added to a stirred solution of 1-bromo-4-iodobenzene(1.33 g, 4.7 mmol) and tetrakis-(triphenylphosphine)palladium(0) (271mg, 5 mol %) in toluene (40 mL). 2N sodium carbonate (4.7 mL, 9.4 mmol)was added and the reaction was heated to 90° C. (oil bath temp.) for 2-3hrs until complete (TLC control).

[0290] The reaction mixture was cooled to room temperature andpartitioned between water and diethyl ether. The phases were separated,the aqueous phase being further extracted with diethyl ether (2×20 mL).The combined extract was washed with water and brine. The etherealsolution was dried over anhydrous MgSO₄, filtered and concentrated invacuo to yield 4-(4-bromophenyl)-dibenzofuran as a yellow solid, whichwas used immediately without further purification.

[0291] A solution of 4-formylphenylboronic acid (0.9 g, 5.64 mmol) inethanol (10 mL) was added to a stirred solution of the crude4-(4-bromophenyl)-dibenzofuran (from the previous reaction) in toluene(40 mL). tetrakis-(Triphenylphosphine)palladium(0) (270 mg, 5 mol %) and2N sodium carbonate (4.7 mL, 9.4 mmol) were added and the reaction washeated to 100® C. (oil bath temp.) for 2-3 hrs until complete (TLCcontrol). The reaction mixture was cooled to room temperature andpartitioned between water and ethyl acetate. The phases were separated,the aqueous phase being further extracted with ethyl acetate (2×20 mL).The combined extract was washed with 0.5 N hydrochloric acid, water andbrine and then dried over anhydrous MgSO₄, filtered and concentrated invacuo. Purification of the product by flash column chromatography, using10-20% ethyl acetate in hexane as eluent, afforded the title compoundhas a white solid (1.51 g).

Example 20

[0292] (4′-Dibenzofuran-4-yl-biphenyl-4-yl)methanol

[0293] Sodium borohydride (322 mg, 8.4 mmol) was added portion-wise to astirred solution of aldehyde (prepared in the previous step) (1.48 g,4.2 mmol) in a mixture of anhydrous THF and ethanol (1:2; 50 mL) at roomtemperature. The reaction mixture was stirred for 5-10 minutes at roomtemperature (TLC control), poured into water (50 mL) and acidified to pH4 with 2N hydrochloric acid, and then extracted with diethyl ether (3×30mL). The combined extract was washed with 0.5 N hydrochloric acid (2×10mL), water and finally brine. The ethereal solution was dried overanhydrous MgSO₄, filtered and concentrated in vacuo. Purification of theproduct by flash column chromatography, using 30% ethyl acetate/hexaneas eluent, afforded the title compound has a white solid (1.40 g).

Example 21

[0294] Methanesulfonic acid, 4′-dibenzofuran-4-yl-biphenyl-4-yl-lmethylEster

[0295] Methanesulfonyl chloride (490 mg, 330 μL, 4.3 mmol) was addeddropwise to a cooled (0° C.) solution of alcohol (prepared in theprevious step) (1.38 g, 3.9 mmol) and triethylamine (800 mg, 1.1 mL, 7.9mmol) in anhydrous methylene chloride (50 mL). The clear reactionmixture was stirred at 0° C. for 2-4 hrs (TLC control), then poured intowater (50 mL), and extracted with diethyl ether (3×30 mL). The combinedextract was washed with 0.5 N hydrochloric acid (2×10 mL), water andfinally brine. The ethereal solution was dried over anhydrous MgSO₄,filtered and concentrated in vacuo. The crude mesylate was used in thesubsequent alkylation step without further purification.

Example 22

[0296](2R)-Methyl-2-tert-butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-propionate.

[0297]L-N-tert-Butoxycarbonyl cysteine methyl ester (940 mg, 4.0 mmol)was added dropwise to a stirred suspension of mesylate (prepared in theprevious step) (1.65 g, 3.8 mmol) and cesium carbonate (2.6 g, 8.0mmol), in anhydrous DMF (50 mL) at room temperature. The reactionmixture was stirred at room temperature for 2-3 hrs (TLC control) andthen poured into water (50 mL) and extracted with diethyl ether (3×50mL). The combined extract was washed with water (2×30 mL), brine (3×30mL), dried over anhydrous MgSO₄, filtered and concentrated in vacuo.Purification of the product by flash column chromatography, using 20-40%ethyl acetate/hexane as eluent, afforded the title compound has a paleyellow solid (1.96 g, 91%): Rf: 0.4 (30% ethyl acetate in heptane).

Example 23

[0298](2R)-2-tert-Butoxycarbonyl-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-propionicAcid.

[0299] 2N Sodium hydroxide solution (1.32 mL, 2.64 mmol) was addeddropwise to a stirred solution of(2R)-methyl-2-tert-butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)propionate(500 mg, 0.88 mmol) in tetrahydrofuran (15 mL) and methanol (3 mL). Theclear reaction mixture was stirred at room temperature until thereaction was complete (TLC control), and then diluted with water (10mL), and acidified to pH 3 with 2N hydrochloric acid. The reactionmixture was extracted with ethyl acetate (2×20 mL). The combined extractwas washed with water, brine, dried over anhydrous MgSO₄, filtered andconcentrated in vacuo. Purification of the product by flash columnchromatography, using 5-10% methanol in methylene chloride as eluent,afforded the title compound has a white solid (420 mg, 87%), m.pt.205-206° C.; Rf: 0.40 (10% methanol in dichloromethane); ¹H NMR(MeOH-d4): δ 7.90 (4H, m, Ar—H), 7.67 (2H, d, J=9 Hz, Ar—H), 7.56 (2H,d, J=9 Hz, Ar—H), 7.53 (2H, d, J=8 Hz, Ar—H), 7.29-7.41 (5H, m, Ar—H),4.34 (1H, m, CHN), 3.87 (2H, s, PhCH₂S), 2.95 (1H, dd, J=15, 5 Hz,CHHCHN), 2.86 (1H, dd, J=15, 7 Hz, CHHCHN), 1.42 (9H, s, CMe₃); ESI-LCMSe/z calcd for C₃₃H₃₁NO₅S 553.676, found 554 (M+H)⁺, 576 (M+Na)⁺.

Example 24

[0300](2R)-2-tert-Butoxycarbonyl-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethylsulfinyl)-propionicAcid.

[0301] Sodium perborate tetrahydrate (42 mg, 0.27 mmol) was added as asolid to a stirred solution of(2R)-2-tert-Butoxycarbonyl-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethyl-sulfanyl)-propionicacid (150 mg, 0.27 mmol), in acetic acid (5 mL) at 40° C. This solutionwas stirred at 40° C. for 1 hour (HPLC control) and then diluted withethyl acetate (50 mL), washed with water, brine (2×), dried overanhydrous MgSO₄, filtered and concentrated in vacuo. Purification bytrituration of the product with diethyl ether afforded the titlecompound as a 1:1 mix of diastereoisomers as a white solid (144 mg,93%): Rf 0.25 (20% methanol in dichloromethane). ¹H NMR (DMSO-d6, 300MHz) δ 8.19 (1H, d, J=8 Hz, Ar—H), 8.15 (1H, dd, J=8, 1 Hz, Ar—H), 8.01(2H, d, J=9 Hz, Ar—H), 7.87 (2H, d, J=9 Hz, Ar—H), 7.78 (4H, m, Ar—H),7.52 (2H, m, Ar—H), 7.44 (4H, m, Ar—H, NH), 4.39 (1H, m, CHN), 4.05-4.27(2H, m, PhCH₂), 3.04 (1H, m, CHHCHN), 2.92 (1H, m, CHHCHN), 1.39 and1.37 (both 4.5H, s, CMe₃ diastereomers); ESI-LCMS e/z calcd forC₃₃H₃₁NO₆S 569.675, found 570 (M+H)⁺, 592 (M+Na)⁺.

Example 25

[0302](2R)-2-tert-Butoxycarbonyl-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethylsulfonyl)-propionicAcid.

[0303] Sodium perborate tetrahydrate (105 mg, 0.68 mmol) was added as asolid to a stirred solution of(2R)-2-tert-Butoxycarbonyl-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethyl-sulfanyl)-propionicacid (150 mg, 0.27 mmol), in acetic acid (10 mL) at 50° C. This solutionwas stirred at 40° C. for 2 hours (HPLC control) and then diluted withethyl acetate (50 mL), washed with water, brine (2×), dried overanhydrous MgSO₄, filtered and concentrated in vacuo. Purification bytrituration of the product with diethyl ether afforded the titlecompound as a white solid (138 mg, 87%): Rf 0.5 (20% methanol indichloromethane). ¹H NMR (MeOH-d4, 300 MHz): δ 7.90 (4H, m, Ar—H), 7.70(4H, m, Ar—H), 7.53 (2H, m, Ar—H), 7.29-7.49 (5H, m, Ar—H), 4.62 (1H, m,CHN) 4.41 (2H, s, PhCH₂S), 3.42 (2H, m, CH ₂CHN), 1.46 (9H, s, CMe₃);ESI-LCMS e/z calcd for C₃₃H₃₁NO₇S 585.674, found 586 (M+H)⁺, 608(M+Na)⁺.

Example 26

[0304](2R)-Methyl-3-(3-bromobenzylsulfanyl)-2-tert-butoxycarbonylamino-propionate.

[0305]L-N-tert-Butoxycarbonyl cysteine methyl ester (1.0 g, 4.25 mmol)was added dropwise to a stirred suspension of 3-bromobenzyl chloride(1.31 g, 6.3 mmol), cesium carbonate (2.77 g, 8.50 mmol) andtetra-n-butyl ammonium iodide (10 mg) in anhydrous DMF (25 mL) at roomtemperature. The reaction mixture was stirred at room temperature for2-3 hrs (TLC control) and then poured into water (50 mL) and extractedwith diethyl ether (3×50 mL). The combined extract was washed with water(2×30 mL), brine (3×30 mL), dried over anhydrous MgSO₄, filtered andconcentrated in vacuo. Purification of the product by flash columnchromatography, using 20-40% ethyl acetate/hexane as eluent, affordedthe title compound has a pale yellow oil (1.54 g, 90%): Rf: 0.4 (30%ethyl acetate in heptane); ¹H NMR (CDCl₃, 300 MHz): δ 7.48 (1H, s,Ar—H), 7.38 (1H, d, J=8 Hz, Ar—H), 7.40 (2H, m, Ar—H), 5.30 (1H, d, J=8Hz, NH), 4.56 (1H, m, CHN), 3.78 (3H, s, OMe), 3.71 (2H, s, PhCH₂S),2.89 (1H, dd, J=13, 5 Hz, CHHCHN), 2.81 (1H, dd, J=13, 5 Hz, CHHCHN),1.49 (9H, s, CMe₃).

Example 27(2R)-Methyl-3-(2-bromobenzylsulfanyl)-2-tert-butoxycarbonylamino-propionate.

[0306]

[0307]L-N-tert-Butoxycarbonyl cysteine methyl ester (1.0 g, 4.25 mmol)was added dropwise to a stirred suspension of 2-bromobenzyl bromide(1.06 g, 4.25 mmol) and cesium carbonate (2.77 g, 8.50 mmol) inanhydrous DMF (25 mL) at room temperature. The reaction mixture wasstirred at room temperature for 2-3 hrs (TLC control) and then pouredinto water (50 mL) and extracted with diethyl ether (3×50 mL). Thecombined extract was washed with water (2×30 mL), brine (3×30 mL), driedover anhydrous MgSO₄, filtered and concentrated in vacuo. Purificationof the product by flash column chromatography, using 20-40% ethylacetate/hexane as eluent, afforded the title compound has a pale yellowoil (1.12 g, 66%): Rf: 0.4 (30% ethyl acetate in heptane); ¹H NMR(CDCl₃, 300 MHz): δ 7.58 (1H, d, J=8 Hz, Ar—H), 7.38 (1H, d, J=8 Hz,Ar—H), 7.32 (1H, t, J=8 Hz, Ar—H), 7.12 (1H, t, J=8 Hz, Ar—H), 5.38 (1H,d, J=8 Hz, NH), 4.58 (1H, m, CHN), 3.86 (3H, s, OMe), 3.77 (2H, s,PhCH₂S), 2.97 (1H, dd, J=13, 5 Hz, CHHCHN), 2.89 (1H, dd, J=13, 5 Hz,CHHCHN), 1.46 (9H, s, CMe₃).

Example 28

[0308](2R)-Methyl-3-(4-bromo-2-fluorobenzylsulfanyl)-2-tert-butoxycarbonylamino-propionate.

[0309]L-N-tert-Butoxycarbonyl cysteine methyl ester (1.0 g, 4.25 mmol)was added dropwise to a stirred suspension of 2-fluoro-4-bromobenzylbromide (1.14 g, 4.25 mmol) and cesium carbonate (2.77 g, 8.50 mmol) inanhydrous DMF (25 mL) at room temperature. The reaction mixture wasstirred at room temperature for 2-3 hrs (TLC control) and then pouredinto water (50 mL) and extracted with diethyl ether (3×50 mL). Thecombined extract was washed with water (2×30 mL), brine (3×30 mL), driedover anhydrous MgSO₄, filtered and concentrated in vacuo. Purificationof the product by flash column chromatography, using 20-40% ethylacetate/hexane as eluent, afforded the title compound has a pale yellowoil (1.12 g, 66%): Rf: 0.25 (30% ethyl acetate in heptane); ¹H NMR(CDCl₃, 300 MHz): δ 7.42 (4H, m, Ar—H), 5.32 (1H, d, J=8 Hz, NH), 4.58(1H, m, CHN), 3.77 (3H, s, OMe), 3.72 (2H, s, PhCH₂S), 2.94 (1H, dd,J=13, 5 Hz, CHHCHN), 2.86 (1H, dd, J=13, 5 Hz, CHHCHN), 1.48 (9H, s,CMe₃)

Example 29

[0310] Suzuki Coupling: General Methods.

[0311] General Method A:

[0312] A solution of 4-(dibenzofuran-4-yl)phenyl boronic acid (5.0 mmol)in methanol (10 mL) was added to a stirred solution of the required arylbromide (4.0 mmol) and tetrakis-(triphenylphosphine)palladium(0) (5 mol%) in toluene (40 mL). 2N sodium carbonate (4 mL, 8.0 mmol) was addedand then the reaction was heated to 80° C. (oil bath temp.) for 2-3 hrsuntil complete (TLC control). The reaction mixture was cooled to roomtemperature and partitioned between water (30 mL) and diethyl ether (50mL). The phases were separated, the aqueous phase being furtherextracted with diethyl ether (2×30 mL). The combined organic extract waswashed with water and brine, dried over anhydrous MgSO₄, filtered andconcentrated in vacuo to yield the coupled product. Purification of theproduct by flash column chromatography, using 20-50% ethylacetate/hexane as eluent, afforded the corresponding methyl ester of thetitle compound.

[0313] 2N Sodium hydroxide (1.0 mL) was added to a stirred solution ofthe amido methyl ester in a mixture of tetrahydrofuran (10 mL) andmethanol (2 mL). The solution was stirred for 1 hour and then acidifiedto pH 3 with 2N hydrochloric acid. The reaction mixture was extractedwith ethyl acetate (3×20 mL). The combined extract was washed withwater, brine, dried over anhydrous MgSO₄, filtered and concentrated invacuo. Purification of the product by flash column chromatography, using5-20% methanol in methylene chloride as eluent, afforded the titlecompound.

[0314] General Method B:

[0315] A suspension of the required aryl bromide (1 mmol),4-(dibenzofuran-4-yl)phenyl boronic acid (1.2 mmol), cesium carbonate(3.0 mmol),[1.1′-bis-(diphenylphodphino)-ferrocene]dichloropalladium(II), complexwith dichloromethane (3 mol %) and 1.1′-bis-(diphenylphodphino)ferrocene(3 mol %) in anhydrous dioxane (20 mL) was heated at reflux for 4-6 hrs(TLC control). Upon reaction completion, the reaction mixture was cooledto room temperature, poured into water (25 mL) and extracted withdiethyl ether (3×30 mL). The combined organic extract was washed withwater and brine, dried over anhydrous MgSO₄, filtered and concentratedin vacuo to yield the coupled product. Purification of the product byflash column chromatography, using 20-50% ethyl acetate/hexane aseluent, afforded the corresponding methyl ester of the title compound.

[0316] 2N Sodium hydroxide (1.0 mL) was added to a stirred solution ofthe amido methyl ester in a mixture of tetrahydrofuran (10 mL) andmethanol (2 mL). The solution was stirred for 1 hour and then acidifiedto pH 3 with 2N hydrochloric acid. The reaction mixture was extractedwith ethyl acetate (3×20 mL). The combined extract was washed withwater, brine, dried over anhydrous MgSO₄, filtered and concentrated invacuo. Purification of the product by flash column chromatography, using5-20% methanol in methylene chloride as eluent, afforded the titlecompound.

Example 30

[0317](2R)-2-tert-Butoxycarbonyl-3-(4′-dibenzofuran-4-yl-biphenyl-3-ylmethylsulfanyl)-propionicAcid.

[0318](2R)-2-tert-Butoxycarbonyl-3-(4′-dibenzofuran-4-yl-biphenyl-3-ylmethylsulfanyl)-propionicacid was prepared according to the method described in Suzuki CouplingMethod A, using(2R)-methyl-3-(3-bromobenzylsulfanyl)-2-tert-butoxycarbonylamino-propionateas the required aryl bromide. The title compound was isolated as a whitesolid: Rf: 0.30 (10% methanol in dichloromethane); ¹H NMR (MeOH-d4, 300MHz): δ 7.93 (4H, m, Ar—H), 7.72 (2H, d, J=9 Hz, Ar—H), 7.58 (4H, m,Ar—H), 7.29-7.41 (5H, m, Ar—H), 4.39 (1H, m, CHN), 3.80 (2H, s, PhCH₂S),2.97 (1H, dd, J=15, 5 Hz, CHHCHN), 2.88 (1H, dd, J=15, 7 Hz, CHHCHN),1.40 (9H, s, CMe₃); ESI-LCMS e/z calcd for C₃₃H₃₁NO₅S 553.676, found 576(M+Na)⁺.

Example 31

[0319](2R)-2-tert-Butoxycarbonyl-3-(4′-dibenzofuran-4-yl-biphenyl-2-ylmethylsulfanyl)-propionicAcid.

[0320](2R)-2-tert-Butoxycarbonyl-3-(4′-dibenzofuran-4-yl-biphenyl-2-ylmethylsulfanyl)-propionicacid was prepared according to the method described in Suzuki CouplingMethod A, using(2R)-methyl-3-(2-bromobenzylsulfanyl)-2-tert-butoxycarbonylamino-propionateas the required aryl bromide. The title compound was isolated as a whitesolid: Rf: 0.30 (10% methanol in dichloromethane); ¹H NMR (CDCl₃, 300MHz): δ 7.97 (4H, q. J=9 Hz, Ar—H), 7.78 (4H, m, Ar—H), 7.42 (2H, m,Ar—H), 7.26-7.41 (5H, m, Ar—H), 4.41 (1H, m, CHN), 3.80 (2H, s, PhCH₂S),2.95 (1H, dd, J=15, 5 Hz, CHHCHN), 2.84 (1H, dd, J=15, 7 Hz, CHHCHN),1.38 (9H, s, CMe₃); ESI-LCMS e/z calcd for C₃₃H₃₁NO₅S 553.676, found 576(M+Na)⁺.

Example 32

[0321](2R)-2-tert-Butoxycarbonyl-3-(4′-dibenzofuran-4-yl-3-fluorobiphenyl-4-ylmethyl-sulfanyl)-propionicAcid.

[0322](2R)-2-tert-Butoxycarbonyl-3-(4′-dibenzofuran-4-yl-3-fluorobiphenyl-4-ylmethyl-sulfanyl)-propionicacid was prepared according to the method described in Suzuki CouplingMethod A, using(2R)-methyl-3-(4-bromo-2-fluorobenzylsulfanyl)-2-tert-butoxycarbonylamino-propionateas the required aryl bromide. The title compound was isolated as a whitesolid: Rf: 0.30 (10% methanol in dichloromethane); ¹H NMR (CDCl₃, 300MHz): δ 7.83 (4H, m, Ar—H), 7.78 (2H, m, Ar—H), 7.64 (2H, m, Ar—H),7.26-7.38 (7H, m, Ar—H), 4.43 (1H, m, CHN), 3.78 (2H, s, PhCH₂S), 3.02(1H, dd, J=15, 5 Hz, CHHCHN), 2.91 (1H, dd, J=15, 7 Hz, CHHCHN), 1.39(9H, s, CMe₃); ESI-LCMS e/z calcd for C₃₃H₃₀FNO₅S 571.666, found 594(M+Na)⁺.

Example 33

[0323](2R)-Methyl-2-amino-3-(4′-dibenzofuran-4-ylbipheny-4-ylmethylsulfanyl)-propionate.

[0324] TMS-I (870 mg, 0.63 mL, 4.35 mmol) was added dropwise to astirred solution of(2R)-methyl-2-tert-butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethyl-sulfanyl)-propionate(2.24 g, 3.96 mmol) in anhydrous methylene chloride (50 mL). Thereaction mixture was stirred at room temperature for 20-30 mins (TLCcontrol), and then diluted with water (50 mL). Saturated sodiumbicarbonate solution was added to adjust the solution to pH 8-9. Thereaction mixture was extracted with diethyl ether (2×50 mL). Thecombined extract was washed with water, brine, dried over anhydrousMgSO₄, filtered and concentrated in vacuo. Purification of the productby flash column chromatography, using 5% methanol in methylene chlorideas eluent, afforded the title compound has a pale yellow solid (1.76 g,95%); Rf: 0.20 (5% methanol in dichloromethane); ¹H NMR (CDCl₃, 300MHz): δ 8.00 (3H, d, J=8 Hz, Ar—H), 7.94 (1H, d, J=8 Hz, Ar—H), 7.76(2H, d, J=9 Hz, Ar—H), 7.64 (4H, m, Ar—H), 7.34-7.51 (5H, m, Ar—H), 3.81(2H, s, PhCH₂S), 3.75 (3H, s, OMe), 3.67 (1H, m CHN), 2.91 (1H, dd,J=15, 5 Hz, CHHCHN), 2.86 (1H, dd, J=15, 8 Hz, CHHCHN), 1.91 (2H, s,NH₂); ESI-LCMS e/z calcd for C₂₉H₂₅NO₃S 467.586, found 468 (M+H)⁺.

Example 34

[0325](2R)-2-Amino-3-(4′-dibenzofuran-4-ylbipheny-4-ylmethylsulfanyl)-propionicAcid.

[0326] 2N Sodium hydroxide (0.5 mL) was added to a stirred solution ofthe amino methyl ester,(2R)-Methyl-2-Amino-3-(4′-dibenzofuran-4-ylbipheny-4-ylmethylsulfanyl)-propionate(100 mg) in a mixture of tetrahydrofuran (5 mL) and methanol (1 mL). Thesolution was stirred for 1 hour and then acidified to pH 3 with 2Nhydrochloric acid. The reaction mixture was extracted with ethyl acetate(3×10 mL). The combined extract was washed with water, brine, dried overanhydrous MgSO₄, filtered and concentrated in vacuo. Purification of theproduct by flash column chromatography, using 25% methanol in methylenechloride as eluent, afforded the title compound as a cream solid (83 mg,86%); Rf: 0.10 (25% methanol in dichloromethane); ¹H NMR (DMSO-d6, 300MHz): δ 11.20 (3H, br s, NH, OH), 7.94 (1H, d, J=9 Hz, Ar—H), 7.91 (1H,d, J=8 Hz, Ar—H), 7.86 (2H, d, J=9 Hz, Ar—H), 7.67 (2H, d, J=9 Hz,Ar—H), 7.48-7.57 (4H, m, Ar—H), 7.21-7.39 (5H, m, Ar—H), 4.02 (1H, dd,J=8, 5 Hz, CHN), 3.74 (2H, s, PhCH₂S), 2.94 (1H, dd, J=16, 5 Hz,CHHCHN), 2.86 (1H, dd, J=16, 8 Hz, CHHCHN); ESI-LCMS e/z calcd forC₂₈H₂₃NO₃S 453.560, found 454 (M+H)⁺.

Example 35

[0327] General Procedure for the Formation of N-Acylated Acids:(N-Acylation and Subsequent Ester Hydrolysis).

[0328] Method A:

[0329] To a solution of(2R)-Methyl-2-amino-3-(4′-dibenzofuran-4-ylbipheny-4-ylmethyl-sulfanyl)-propionate(140 mg, 0.296 mmol) in a mixture of methylene chloride (5 mL) anddimethylformamide (1 mL) was added the carboxylic acid (0.37 mmol), EDCI(85 mg, 0.43 mmol), HOBt (5 mg) and triethylamine (82 μL). The reactionmixture was stirred for 16 hours and then diluted with diethyl ether (25mL), washed with water, brine (2×), dried over anhydrous MgSO₄, filteredand concentrated in vacuo to yield the crude amido-methyl estercompound.

[0330] 2N Sodium hydroxide (0.5 mL) was added to a stirred solution ofthe amido methyl ester in a mixture of tetrahydrofuran (5 mL) andmethanol (1 mL). The solution was stirred for 1 hour and then acidifiedto pH 3 with 2N hydrochloric acid. The reaction mixture was extractedwith ethyl acetate (3×10 mL). The combined extract was washed withwater, brine, dried over anhydrous MgSO₄, filtered and concentrated invacuo. Purification of the product by flash column chromatography, using5-20% methanol in methylene chloride as eluent, afforded the titlecompound.

[0331] Method B:

[0332] To a solution of(2R)-Methyl-2-amino-3-(4′-dibenzofuran-4-ylbipheny-4-ylmethyl-sulfanyl)-propionate(140 mg, 0.296 mmol) and triethylamine (75 mg, 0.10 mL, 0.74 mmol) in a1,2-dichloroethane was added the required acylating reagent (acidchloride, sulfonyl chloride, carbamoyl chloride or isocyanate) (0.37mmol). The reaction mixture was stirred for 4 hours and then dilutedwith diethyl ether (25 mL), washed with water, brine (2×), dried overanhydrous MgSO₄, filtered and concentrated in vacuo to yield the crudeamido-methyl ester compound.

[0333] 2N Sodium hydroxide (0.5 mL) was added to a stirred solution ofthe amido methyl ester in a mixture of tetrahydrofuran (5 mL) andmethanol (1 mL). The solution was stirred for 1 hour and then acidifiedto pH 3 with 2N hydrochloric acid. The reaction mixture was extractedwith ethyl acetate (3×10 mL). The combined extract was washed withwater, brine, dried over anhydrous MgSO₄, filtered and concentrated invacuo. Purification of the product by flash column chromatography, using5-20% methanol in methylene chloride as eluent, afforded the titlecompound.

Example 36

[0334](2R)-3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-2-(2,4-difluorobenzoyl-amino)-propionicAcid.

[0335](2R)-3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-2-(2,4-difluorobenzoyl-amino)-propionicacid was prepared according to the method described in Example 35,Method A, using 2,4-difluorobenzoic acid as the corresponding carboxylicacid. The title compound was isolated as a white solid: Rf=0.60 (20%methanol in dichloromethane). ¹H NMR (DMSO-d6, 300 MHz): δ 8.21 (1H, d,J=8 Hz, Ar—H), 8.15 (1H, d, J=8 Hz, Ar—H), 7.98 (2H, d, J=9 Hz, Ar—H),7.82 (2H, d, J=9 Hz, Ar—H), 7.74 (2H, d, J=8 Hz, Ar—H), 7.65 (2H, d, J=8Hz, Ar—H), 7.50 (2H, m, Ar—H), 7.38 (5H, m, Ar—H, NH), 7.19 (2H, t, J=9Hz, Ar—H), 4.30 (1H, m, CHN), 3.80 (1H, d, J=15 Hz, PhCHHS), 3.73 (1H,d, J=15 Hz, PhCHHS), 3.07 (1H, dd, J=15, 5 Hz, CHHCHN), 2.95 (1H, dd,J=15, 7 Hz, CHHCHN); ESI-LCMS e/z calcd for C₃₅H₂₅F₂NO₄S 593.648, found594 (M+H)⁺, 616 (M+Na)⁺.

Example 37

[0336](2R)-3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-2-(4-nitrobenzoyl-amino)-propionicAcid.

[0337](2R)-3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-2-(4-nitrobenzoyl-amino)-propionicacid was prepared according to the method described in Example 35,Method A, using 4-nitrobenzoic acid as the corresponding carboxylicacid. The title compound was isolated as a pale yellow solid: Rf=0.40(20% methanol in dichloromethane). ¹H NMR (DMSO-d6, 300 MHz): δ 9.10(1H, d, J=9 Hz, NH), 8.32 (2H, d, J=9 Hz, Ar—H), 8.17(2H, dd, J=13, 8Hz, Ar—H), 8.10 (2H, d, J=9 Hz, Ar—H), 7.98 (2H, d, J=9 Hz, Ar—H), 7.84(2H, d, J=9 Hz, Ar—H), 7.72 (4H, m, Ar—H), 7.50 (2H, q, J=9 Hz, Ar—H),7.42 (3H, m, Ar—H), 4.62 (1H, m, CHN), 3.85 (2H, s, PhCH₂S), 3.01 (1H,dd, J=15, 5 Hz, CHHCHN), 2.89 (1H, dd, J=15, 11 Hz, CHHCHN); ESI-LCMSe/z calcd for C₃₅H₂₆N₂O₆S 602.664, found 603 (M+H)⁺.

Example 38

[0338](2R)-3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-2-[(pyridine-3-carbonyl)-amino]-propionicAcid.

[0339](2R)-3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-2-[(pyridine-3-carbonyl)-amino]-propionicacid was prepared according to the method described in Example 35,Method A, using nicotinic acid as the corresponding carboxylic acid. Thetitle compound was isolated as a white solid: Rf=0.40 (20% methanol indichloromethane). ¹H NMR (DMSO-d6, 300 MHz): δ 9.02 (2H, m, Ar—H, NH),8.71 (2H, dd, J=5, 2 Hz, Ar—H), 8.19 (3H, m, Ar—H), 8.01 (2H, d, J=9 Hz,Ar—H), 7.84 (2H, d, J=9 Hz, Ar—H), 7.74 (4H, m, Ar—H), 7.52 (3H, m,Ar—H), 7.42 (3H, m, Ar—H), 4.65 (1H, m, CHN), 3.85 (2H, s, PhCH₂S), 3.00(1H, dd, J=15, 5 Hz, CHHCHN), 2.89 (1H, dd, J=15, 11 Hz, CHHCHN);ESI-LCMS e/z calcd for C₃₄H₂₆N₂O₄S 558.655, found 559 (M+H)⁺.

Example 39

[0340]N-[1-Carboxy-2-(4′-dibenzofuran-4-ylbiphen-4-ylmethylsulfanyl)-ethyl]-tere-phthalamicAcid.

[0341]N-[1-Carboxy-2-(4′-dibenzofuran-4-ylbiphen-4-ylmethylsulfanyl)-ethyl]-tere-phthalamicacid was prepared according to the method described in Example 35,Method A, using terephthalic acid as the corresponding carboxylic acid.The title compound was isolated as a white solid: Rf=0.10 (20% methanolin dichloromethane). ¹H NMR (DMSO-d6, 300 MHz): δ 8.95 (1H, d, J=9 Hz,NH), 8.26 (2H, d, J=9 Hz, Ar—H), 8.10 (2H, dd, J=13, 8 Hz, Ar—H), 7.98(4H, m, Ar—H), 7.84 (2H, d, J=9 Hz, Ar—H), 7.72 (3H, m, Ar—H), 7.45-7.58(6H, m, Ar—H) 4.61 (1H, m, CHN), 3.83 (2H, s, PhCH₂S), 3.00 (1H, dd,J=15, 5 Hz, CHHCHN), 2.89 (1H, dd, J=15, 11 Hz, CHHCHN); ESI-LCMS e/zcalcd for C₃₆H₂₇NO₆S 601.676, found 602 (M+H)⁺, 624 (M+Na)⁺.

Example 40

[0342](2R)-2-Benzoylamino-3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-propionicAcid.

[0343](2R)-2-Benzoylamino-3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-propionicacid was prepared according to the method described in Example 35,Method A, using benzoic acid as the corresponding carboxylic acid. Thetitle compound was isolated as a white solid: Rf=0.50 (20% methanol indichloromethane). ¹H NMR (DMSO-d6, 300 MHz): δ 8.18 (2H, d, J=8 Hz,Ar—H), 8.13 (1H, dd, J=8, 1 Hz, Ar—H), 7.97 (2H, d, J=9 Hz, Ar—H), 7.84(4H, m, Ar—H), 7.74 (2H, m, Ar—H), 7.66 (2H, d, J=9 Hz, Ar—H), 7.38-7.56(8H, m, Ar—H, NH), 4.39 (1H, m, CHN), 3.81 (1H, d, J=15 Hz, PhCHHS),3.75 (1H, d, J=15 Hz, PhCHHS), 3.09 (1H, dd, J=13, 8 Hz, CHHCHN), 2.92(1H, dd, J=15, 8 Hz, CHHCHN); ESI-LCMS e/z calcd for C₃₅H₂₇NO₄S 557.667,found 558 (M+H)⁺, 580 (M+Na)⁺.

Example 41

[0344](2R)-3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-2-(2-fluoro-5-trifluoromethylbenzoylamino)-propionicAcid.

[0345](2R)-3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-2-(2-fluoro-5-trifluoro-methylbenzoylamino)-propionicacid was prepared according to the method described in Example 35,Method A, using 2-fluoro-5-trifluoromethlybenzoic acid as thecorresponding carboxylic acid. The title compound was isolated as awhite solid: Rf=0.60 (20% methanol in dichloromethane). ¹H NMR (DMSO-d6,300 MHz): δ 8.45 (1H, t, J=7 Hz, Ar—H), 8.18 (1H, d, J=8 Hz, Ar—H), 8.13(1H, d, J=8 Hz, Ar—H), 8.05 (1H, d, J=7 Hz, Ar—H), 7.97 (3H, m, Ar—H),7.82 (2H, d, J=9 Hz, Ar—H), 7.74 (2H, d, J=9 Hz, Ar—H), 7.66 (2H, d, J=9Hz, Ar—H), 7.54 (4H, m, Ar—H, NH), 7.42 (2H, m, Ar—H), 4.34 (1H, m,CHN), 3.80 (1H, d, J=15 Hz, PhCHHS), 3.76 (1H, d, J=15 Hz, PhCHHS), 3.09(1H, dd, J=15, 7 Hz, CHHCHN), 2.92 (1H, dd, J=15, 7 Hz, CHHCHN);ESI-LCMS e/z calcd for C₃₆H₂₅F₄NO₄S 643.654, found 644 (M+H)⁺, 666(M+Na)⁺.

Example 42

[0346](2R)-3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-2-(2-fluoro-4-trifluoromethylbenzoylamino)-propionicAcid.

[0347](2R)-3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-2-(2-fluoro-4-trifluoromethylbenzoylamino)-propionicacid was prepared according to the method described in Example 35,Method A, using 2-fluoro-4-trifluoromethlybenzoic acid as thecorresponding carboxylic acid. The title compound was isolated as awhite solid: Rf=0.60 (20% methanol in dichloromethane). ¹H NMR (DMSO-d6,300 MHz): δ 8.41 (1H, t, J=7 Hz, Ar—H), 8.18 (1H, dd, J=8, 1 Hz, Ar—H),8.15 (1H, d, J=9 Hz, Ar—H), 7.97-8.05 (3H, m, Ar—H), 7.82 (3H, m, Ar—H),7.74 (2H, d, J=8 Hz, Ar—H), 7.66 (3H, m, Ar—H), 7.40-7.52 (5H, m, Ar—H,NH), 4.34 (1H, m, CHN), 3.81 (1H, d, J=15 Hz, PhCHHS), 3.76 (1H, d, J=15Hz, PhCHHS), 3.10 (1H, dd, J=15, 5 Hz, CHHCHN), 2.92 (1H, dd, J=15, 7Hz, CHHCHN); ESI-LCMS e/z calcd for C₃₆H₂₅F₄NO₄S 643.654, found 666(M+Na)⁺.

Example 43

[0348](2R)-3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-2-(4-fluorophenylacetyl-amino)-propionicacid.

[0349](2R)-3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-2-(4-fluorophenylacetylamino)-propionicacid was prepared according to the method described in Example 35,Method A, using 4-fluorophenylacetic acid as the correspondingcarboxylic acid. The title compound was isolated as a white solid:Rf=0.15 (10% methanol in dichloromethane). ¹H NMR (DMSO-d6, 300 MHz): δ8.19 (1H, d, J=8 Hz, Ar—H), 8.15 (1H, dd, J=9, 1 Hz, Ar—H), 8.00 (2H, d,J=9 Hz, Ar—H), 7.91 (1H, m, NH), 7.84 (2H, d, J=9 Hz, Ar—H), 7.74 (2H,d, J=8 Hz, Ar—H), 7.66 (2H, d, J=9 Hz, Ar—H), 7.30-7.56 (7H, m, Ar—H),7.09 (2H, m, Ar—H), 4.20 (1H, m, CHN), 3.75 (1H, d, J=15 Hz, PhCHHS),3.69 (1H, d, J=15 Hz, PhCHHS), 3.53 (1H, d, J=15 Hz, PhCHHCO), 3.49 (1H,d, J=15 Hz, PhCHHCO), 2.90 (1H, dd, J=15, 5 Hz, CHHCHN), 2.74 (1H, dd,J=15, 8 Hz, CHHCHN); ESI-LCMS e/z calcd for C₃₆H₂₈FNO₄S 589.684, found590 (M+H)⁺.

Example 44

[0350](2R)-3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-2-(4-methoxybenzoyl-amino)-propionicAcid.

[0351](2R)-3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-2-(4-methoxybenzoyl-amino)-propionicacid was prepared according to the method described in Example 35,Method A, using 4-methoxybenzoic acid as the corresponding carboxylicacid. The title compound was isolated as a white solid: Rf=0.20 (10%methanol in dichloromethane). ¹H NMR (DMSO-d6, 300 MHz): δ 8.18 (1H, d,J=8 Hz, Ar—H), 8.13 (1H, dd, J=8, 1 Hz, Ar—H), 8.04 (1H, m, NH), 7.97(2H, d, J=9 Hz, Ar—H), 7.82 (4H, t, J=10 Hz, Ar—H), 7.72 (2H, dd, J=9, 4Hz, Ar—H), 7.64 (2H, d, J=9 Hz, Ar—H), 7.38-7.56 (5H, m, Ar—H), 6.99(2H, d, J=9 Hz, Ar—H), 4.41 (1H, m, CHN), 3.79 (2H, s, PhCH₂S), 3.08(1H, dd, J=15, 5 Hz, CHHCHN), 2.92 (1H, dd, J=15, 8 Hz, CHHCHN);ESI-LCMS e/z calcd for C₃₆H₂₉NO₅S 587.693, found 588 (M+H)⁺, 610(M+Na)⁺.

Example 45

[0352](2R)-3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-2-(2,4,6-trifluoro-benzoyl-amino)-propionicAcid.

[0353](2R)-3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-2-(2,4,6-trifluoro-benzoyl-amino)-propionicacid was prepared according to the method described in Example 35,Method A, using 2,4,6-trifluorobenzoic acid as the correspondingcarboxylic acid. The title compound was isolated as a white solid:Rf=0.15 (10% methanol in dichloromethane). ¹H NMR (DMSO-d6, 300 MHz): δ8.41 (1H, d, J=8 Hz, Ar—H), 8.18 (1H, d, J=8 Hz, Ar—H), 8.15 (1H, d, J=9Hz, Ar—H), 7.98 (2H, d, J=8 Hz, Ar—H), 7.82 (2H, d, J=8 Hz, Ar—H), 7.72(4H, m, Ar—H), 7.46 (5H, m, Ar—H, NH), 7.20 (2H, t, J=9 Hz, Ar—H), 4.38(1H, m, CHN), 3.81 (1H, d, J=15 Hz, PhCHHS), 3.76 (1H, d, J=15 Hz,PhCHHS), 3.06 (1H, dd, J=15, 5 Hz, CHHCHN), 2.84 (1H, dd, J=15, 8 Hz,CHHCHN); ESI-LCMS e/z calcd for C₃₅H₂₄F₃NO₄S 611.638, found 612 (M+H)⁺,634 (M+Na)⁺.

Example 46

[0354] (2R, 2′S)-2-[(1-Acetylpyrollidine-2-carbonyl)amino]-3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-propionicAcid.

[0355] (2R, 2′S)-2-[(1-Acetylpyrollidine-2-carbonyl)amino]-3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-propionicacid was prepared according to the method described in Example 35,Method A, using L-N-acetylproline as the corresponding carboxylic acid.The title compound was isolated as a white solid: Rf=0.05 (15% methanolin dichloromethane). ¹H NMR (DMSO-d6, 300 MHz): δ 8.41 (1H, d, J=8 Hz,NH), 8.18 (1H, d, J=8 Hz, Ar—H), 8.15 (1H, d, J=9 Hz, Ar—H), 8.02 (2H,d, J=8 Hz, Ar—H), 7.82 (2H, d, J=8 Hz, Ar—H), 7.72 (4H, m, Ar—H), 7.58(2H, m, Ar—H), 7.40 (3H, m, Ar—H), 4.40 (2H, m, 2×CHN), 3.81 (2H, s,PhCH₂S), 3.50 (2H, m, CH₂N), 2.96 (1H, dd, J=15, 5 Hz, CHHCHN), 2.84(1H, dd, J=15, 8 Hz, CHHCHN), 2.21 (1H, m), 1.98 (3H, s, CH₃CO), 1.88(3H, m); ESI-LCMS e/z calcd for C₃₅H₃₂N₂O₅S 592.713, found 593 (M+H)⁺,615 (M+Na)⁺.

Example 47

[0356](2R)-3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-2-(2phenylamino-acetyl-amino)-propionicAcid.

[0357](2R)-3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-2-(2phenylamino-acetyl-amino)-propionicacid was prepared according to the method described in Example 35,Method A, using 2-phenylaminoacetic acid as the corresponding carboxylicacid. The title compound was isolated as a white solid: Rf=0.20 (20%methanol in dichloromethane). ¹H NMR (DMSO-d6, 300 MHz): δ 8.18 (1H, d,J=8 Hz, Ar—H), 8.13 (1H, d, J=9 Hz, Ar—H), 7.99 (2H, d, J=9 Hz, Ar—H),7.82 (3H, d, J=9 Hz, Ar—H), 7.74 (2H, d, J=7 Hz, Ar—H), 7.67 (2H, d, J=9Hz, Ar—H), 7.52 (2H, m, Ar—H), 7.40 (4H, m, Ar—H, NH), 7.06 (2H, t, J=9Hz, Ar—H), 6.58 (2H, d, J=9 Hz, Ar—H) 6.09 (1H, t, J=6 Hz, NH), 4.19(1H, m, CHN), 3.75 (1H, d, J=15 Hz, PhCHHS), 3.71 (1H, d, J=15 Hz,PhCHHS), 3.62 (2H, m, CH₂N), 2.96 (1H, dd, J=15, 5 Hz, CHHCHN), 2.92(1H, dd, J=15, 6 Hz, CHHCHN); ESI-LCMS e/z calcd for C₃₆H₃₀N₂O₄S586.709, found 588 (M+H)⁺, 609 (M+Na)⁺.

Example 48

[0358](2R)-3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-2-[2-(3-(trifluoromethyl-phenyl)-acetylamino]-propionicAcid.

[0359](2R)-3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-2-[2-(3-(trifluoromethyl-phenyl)-acetylamino]-propionicacid was prepared according to the method described in Example 35,Method A, using 2-(3-trifluoromethylphenyl)acetic acid as thecorresponding carboxylic acid. The title compound was isolated as awhite solid: Rf=0.40 (10% methanol in dichloromethane). ¹H NMR (DMSO-d6,300 MHz): δ 8.17 (3H, dd, J=14, 9 Hz, Ar—H), 8.00 (2H, d, J=9 Hz, Ar—H),7.82 (2H, d, J=9 Hz, Ar—H), 7.74 (2H, d, J=8 Hz, Ar—H), 7.66 (3H, m,Ar—H), 7.56 (5H, m, Ar-H, NH), 7.41 (1H, t, J=8 Hz, Ar—H), 7.32 (2H, d,J=9 Hz, Ar—H), 4.27 (1H, m, CHN), 3.70 (4H, m, PhCH₂S+PhCH₂CO), 2.91(1H, dd, J=15, 5 Hz, CHHCHN), 2.76 (1H, dd, J=15, 8 Hz, CHHCHN);ESI-LCMS e/z calcd for C₃₇H₂₈F₃NO₄S 639.691, found 662 (M+Na)⁺.

Example 49

[0360](2R)-3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-2-[(1,5-dimethyl-1H-pyrazole-3-carbonyl)-amino]-propionicAcid.

[0361](2R)-3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-2-[(1,5-dimethyl-1H-pyrazole-3-carbonyl)-amino]-propionicacid was prepared according to the method described in Example 35,Method A, using 1,5-dimethyl-1H-pyrazole-3-carboxylic acid as thecorresponding carboxylic acid. The title compound was isolated as awhite solid: Rf=0.30 (10% methanol in dichloromethane). ¹H NMR (DMSO-d6,300 MHz): δ 8.18 (1H, d, J=9 Hz, Ar—H), 8.14 (1H, dd, J=9, 1 Hz, Ar—H),7.99 (2H, d, J=9 Hz, Ar—H), 7.91 (1H, d, J=8 Hz, NH), 7.82 (2H, d, J=9Hz, Ar—H), 7.74 (2H, m, Ar—H), 7.66 (2H, d, J=9 Hz, Ar—H), 7.52 (2H, m,Ar—H), 7.40 (3H, m, Ar—H), 6.41 (1H, s, pyrazole-CH), 4.36 (1H, m, CHN),3.76 (5H, m, PhCH₂S+NMe), 3.10 (1H, dd, J=15, 5 Hz, CHHCHN), 2.95 (1H,dd, J=15, 8 Hz, CHHCHN), 2.26 (3H, s, Me); ESI-LCMS e/z calcd forC₃₄H₂₉N₃O₄S 575.686, found 598 (M+Na)⁺.

Example 50

[0362](1′R)-N-[2-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-1-methoxycarbonyl-ethyl]-succinamicAcid

[0363](1′R)-N-[2-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-1-methoxycarbonyl-ethyl]-succinamicacid was prepared according to the method described in Example 35,Method B, using succinic anhydride as the corresponding acylatingreagent. The title compound was isolated, as the mono-methyl ester, asan off-white solid: Rf=0.40 (10% methanol in dichloromethane). ¹H NMR(DMSO-d6, 300 MHz): δ 8.45 (1H, d, J=9 Hz, NH), 8.19 (1H, d, J=9 Hz,Ar—H), 8.15 (1H, dd, J=9, 1 Hz, Ar—H), 8.01 (2H, d, J=9 Hz, Ar—H), 7.86(2H, d, J=9 Hz, Ar—H), 7.74 (4H, m, Ar—H), 7.53 (2H, m, Ar—H), 7.42 (3H,m, Ar—H), 4.52 (1H, m, CHN), 3.82 (2H, s, PhCH₂S), 3.64 (3H, s, OMe),2.82 (1H, dd, J=15, 7 Hz, CHHCHN), 2.71 (1H, dd, J=15, 8 Hz, CHHCHN),2.41 (4H, m, CH₂CH₂); ESI-LCMS e/z calcd for C₃₃H₂₉NO₆S 567.659, found568 (M+H)⁺, 590 (M+Na)⁺.

Example 51

[0364](1′R)-N-[1-Carboxy-2-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-1-ethyl]-succinamicAcid.

[0365](1′R)-N-[1-Carboxy-2-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-1-ethyl]-succinamicacid was prepared by hydrolysis of(1′R)-N-[2-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-1-methoxycarbonyl-ethyl]-succinamicacid (prepared above) according to the hydrolysis conditions describedin Example 35, method B. The title compound was isolated as a whitesolid: Rf=0.20 (20% methanol in dichloromethane). ¹H NMR (DMSO-d6, 300MHz): δ 8.31 (1H, d, J=9 Hz, NH), 8.19 (1H, d, J=9 Hz, Ar—H), 8.15 (1H,dd, J=9, 1 Hz, Ar—H), 8.00 (2H, d, J=9 Hz, Ar—H), 7.85 (2H, d, J=9 Hz,Ar—H), 7.73 (4H, m, Ar—H), 7.53 (2H, m, Ar—H), 7.42 (3H, m, Ar—H), 4.47(1H, m, CHN), 3.82 (2H, s, PhCH₂S), 3.64 (3H, s, OMe), 2.81 (1H, dd,J=15, 6 Hz, CHHCHN), 2.69 (1H, dd, J=15, 9 Hz, CHHCHN), 2.42 (4H, m,CH₂CH₂); ESI-LCMS e/z calcd for C₃₂H₂₇NO₆S 553.632, found 554 (M+H)⁺.

Example 52

[0366](2R)-3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-2-(4-fluorobenzoyl-amino)-propionicAcid.

[0367](2R)-3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-2-(4-fluorobenzoyl-amino)-propionicacid was prepared according to the method described in Example 35,Method A, using 4-fluorobenzoic acid as the corresponding carboxylicacid. The title compound was isolated as a white solid: Rf=0.30 (10%methanol in dichloromethane). ¹H NMR (DMSO-d6, 300 MHz): δ 8.37 (1H, d,J=8 Hz, NH), 8.18 (1H, d, J=9 Hz, Ar—H), 8.15 (1H, d, J=8 Hz, Ar—H),7.98 (4H, m, Ar—H), 7.82 (2H, d, J=9 Hz, Ar—H), 7.73 (2H, m, Ar—H), 7.66(2H, d, J=9 Hz, Ar—H), 7.48 (3H, m, Ar—H, NH), 7.42 (2H, d, J=8 Hz,Ar—H), 7.28 (2H, t, J=9 Hz, Ar—H), 4.45 (1H, m, CHN), 3.78 (2H, s,PhCH₂S), 3.07 (1H, dd, J=15, 5 Hz, CHHCHN), 2.84 (1H, dd, J=15, 9 Hz,CHHCHN); ESI-LCMS e/z calcd for C₃₅H₂₆FNO₄S 575.657, found 576 (M+H)⁺.

Example 53

[0368](1′R)-N-[2-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-1-methoxycarbonyl-ethyl]-phthalamicAcid.

[0369](1′R)-N-[2-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-1-methoxycarbonyl-ethyl]-phthalamicacid was prepared according to the method described in Example 35,Method B, using phthalic anhydride as the corresponding acylatingreagent. The title compound was isolated, as the mono-methyl ester, as awhite solid: Rf=0.20 (5% methanol in dichloromethane). ¹H NMR (CDCl₃,300 MHz): δ 8.76 (4H, m, Ar—H), 7.64 (2H, d, J=9 Hz, Ar—H), 7.58 (4H, m,Ar—H), 7.42 (4H, m, Ar—H), 7.32 (5H, m, Ar—H), 4.98 (1H, m, CHN), 3.78(2H, s, PhCH₂S), 3.62 (3H, s, OMe), 3.02 (1H, dd, J=15, 7 Hz, CHHCHN),2.90 (1H, dd, J=15, 8 Hz, CHHCHN); ESI-LCMS e/z calcd for C₃₇H₂₉NO₆S615.703, found 617 (M+H)⁺.

Example 54

[0370](1′R)-N-[1-Carboxy-2-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-ethyl]-phthalamicacid.

[0371](1′R)-N-[1-Carboxy-2-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-ethyl]-phthalamicacid was prepared by hydrolysis of(1′R)-N-[2-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-1-methoxycarbonyl-ethyl]-phthalamicacid (prepared above) according to the hydrolysis conditions describedin Example 35, method B. The title compound was isolated as a whitesolid: Rf=0.05 (20% methanol in dichloromethane). ¹H NMR (DMSO-d6, 300MHz): δ 8.76 (1H, d, J=9 Hz, NH), 8.19 (1H, d, J=9 Hz, Ar—H), 8.15 (1H,dd, J=9, 1 Hz, Ar—H), 8.00 (2H, d, J=9 Hz, Ar—H), 7.86 (2H, d, J=9 Hz,Ar—H), 7.73 (5H, m, Ar—H), 7.56 (2H, m, Ar—H), 7.48 (6H, m, Ar—H), 4.62(1H, m, CHN), 3.86 (2H, s, PhCH₂S), 2.92 (1H, dd, J=15, 6 Hz, CHHCHN),2.69 (1H, dd, J=15, 9 Hz, CHHCHN); ESI-LCMS e/z calcd for C₃₆H₂₇NO₆S601.676, found 603 (M+H)⁺.

Example 55

[0372](2R)-2-(4-Cyanobenzoylamino-3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethyl-sulfanyl)-propionicAcid.

[0373](2R)-2-(4-Cyanobenzoylamino-3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethyl-sulfanyl)-propionicacid was prepared according to the method described in Example 35,Method A, using 4-cyanobenzoic acid as the corresponding carboxylicacid. The title compound was isolated as a white solid: Rf=0.50 (20%methanol in dichloromethane). ¹H NMR (DMSO-d6, 300 MHz): δ 8.59 (1H, d,J=8 Hz, NH), 8.26 (1H, s, Ar—H), 8.16 (2H, m, Ar—H), 8.10 (1H, d, J=8Hz, Ar—H), 7.93 (3H, m, Ar—H), 7.76 (2H, d, J=9 Hz, Ar—H), 7.68 (2H, m,Ar—H), 7.62 (2H, d, J=9 Hz, Ar—H), 7.38-7.48 (3H, m, Ar—H), 7.34 (3H, m,Ar—H), 4.46 (1H, m, CHN), 3.77 (2H, s, PhCH₂S), 3.05 (1H, dd, J=15, 5Hz, CHHCHN), 2.84 (1H, dd, J=15, 8 Hz, CHHCHN); ESI-LCMS e/z calcd forC₃₆H₂₆N₂O₄S 582.677, found 605 (M+Na)⁺.

Example 56

[0374](2R)-3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-2-(3,3-dimethylbutyryl-amino)-propionicacid.

[0375](2R)-3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-2-(3,3-dimethylbutyryl-amino)-propionicacid was prepared according to the method described in Example 35,Method A, using 3,3-dimethylbutyric acid as the corresponding carboxylicacid. The title compound was isolated as a pale yellow solid: Rf=0.30(10% methanol in dichloromethane). ¹H NMR (DMSO-d6, 300 MHz): δ 8.24(1H, d, J=8 Hz, NH), 8.17 (2H, t, J=9 Hz, Ar—H), 8.04 (2H, d, J=8 Hz,Ar—H), 7.90 (2H, d, J=9 Hz, Ar—H), 7.76 (4H, m, Ar—H), 7.56 (2H, q, J=9Hz, Ar—H), 7.44 (3H, m, Ar—H), 4.48 (1H, m, CHN), 3.85 (2H, s, PhCH₂S),2.86 (1H, dd, J=15, 5 Hz, CHHCHN), 2.71 (1H, dd, J=15, 9 Hz, CHHCHN),2.06 (2H, s, CH₂CO), 0.99 (9H, s, CMe₃) ESI-LCMS e/z calcd forC₃₄H₃₃NO₄S 551.704, found 552 (M+H)⁺, 574 (M+Na)⁺.

Example 57

[0376](2R)-2-(3-tert-Butyl-ureido)-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-propionicAcid.

[0377](2R)-2-(3-tert-Butyl-ureido)-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-propionicacid was prepared according to the method described in Example 35,Method B, using tert-butyl isocyanate as the corresponding acylatingreagent. The title compound was isolated as a colorless foam: Rf=0.10(10% methanol in dichloromethane). ¹H NMR (DMSO-d6, 300 MHz): δ 8.19(1H, d, J=8 Hz, Ar—H), 8.13 (1H, dd, J=9, 1 Hz, Ar—H), 7.98 (2H, d, J=9Hz, Ar—H), 7.84 (2H, d, J=9 Hz, Ar—H), 7.74 (2H, m, Ar—H), 7.67 (2H, d,J=9 Hz, Ar—H), 7.53 (2H, m, Ar—H), 7.42 (3H, m, Ar—H), 6.28 (1H, s, NH),6.06 (1H, d, J=8 Hz, NH), 4.13 (1H, m, CHN), 3.78 (2H, s, PhCH₂S), 2.86(1H, dd, J=15, 5 Hz, CHHCHN), 2.75 (1H, dd, J=15, 6 Hz, CHHCHN), 1.24(9H, s, CMe₃); ESI-LCMS e/z calcd for C₃₃H₃₂N₂O₄S 552.692, found 553(M+H)⁺.

Example 58

[0378](2R)-2-[2,3-bis-(tert-Butoxycarbonyl)guanidino]-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-propionicAcid.

[0379](2R)-2-[2,3-bis-(tert-Butoxycarbonyl)guanadino)]-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-propionicacid was prepared according to the method described in Example 35,Method B, usingN,N′-bis-(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine as thecorresponding acylating reagent. The title compound was isolated as anoff-white solid: Rf=0.40 (10% methanol in dichloromethane). ¹H NMR(CDCl₃, 300 MHz): δ 11.13 (1H, s, NH), 9.06 (1H, s, NH), 7.96 (4H, m,Ar—H), 7.74 (2H, d, J=9 Hz, Ar—H), 7.62 (4H, d, J=8 Hz, Ar—H), 7.46 (3H,m, Ar—H), 7.36 (2H, m, Ar—H), 4.65 (1H, m, CHN), 3.86 (2H, s, PhCH₂S),3.10 (2H, m, CH ₂CHN), 1.54 (9H, s, CMe₃), 1.48 (9H, s, CMe₃); ESI-LCMSe/z calcd for C₃₉H₄₁N₃O₇S 695.833, found 696 (M+H)⁺, 718 (M+Na)⁺.

Example 59

[0380](2R)-3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-2-guanidino-propionicAcid.

[0381] Trifluoroacetic acid (2 mL) was added to a stirred solution of(2R)-2-[2,3-bis-(tert-butoxycarbonyl)guanidino]-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-propionicacid (250 mg, 0.36 mmol) in anhydrous dichloromethane (10 mL). Thereaction was stirred for 4 hours (HPLC control) and then concentrated invacuo. The resultant brown oil was reconstituted and concentrated frommethanol (3×10 mL) and then from dichloromethane (2×10 mL) to give thetitle compound as an off-white solid (175 mg, 99%): Rf=0.20 (10%methanol in dichloromethane). ¹H NMR (DMSO-d6, 300 MHz): δ 8.19 (1H, d,J=8 Hz, Ar—H), 8.13 (1H, d, J=9 Hz, Ar—H), 8.02 (2H, d, J=9 Hz, Ar—H),7.84 (3H, m, Ar—H), 7.74 (4H, m, 2×Ar—H, 2×NH), 7.53 (3H, m, Ar—H), 7.42(3H, m, Ar—H), 7.26 (1H, d, J=9 Hz, NH), 7.10 (1H, br s, NH), 4.58 (1H,m, CHN), 3.86 (2H, s, PhCH₂S), 2.92 (1H, dd, J=15, 5 Hz, CHHCHN), 2.75(1H, dd, J=15, 7 Hz, CHHCHN); ESI-LCMS e/z calcd for C₂₉H₂₅N₃O₃S495.600, found 496 (M+H)⁺.

Example 60

[0382](2R)-3-(4′-Dibenzofuran-4-ylbiphen-4-ylmethylsulfanyl)-2-(4-trifluoromethylbenzyl-amino)-propionicacid.

[0383] Sodium nitrite (31 mg, 0.45 mmol) was added portion-wise to astirred slurry of(2R)-methyl-2-amino-3-(4′-dibenzofuran-4-ylbipheny-4-ylmethylsulfanyl)-propionate(140 mg, 0.3 mmol) and potassium bromide (180 mg, 1.5 mmol) in 2Nsulfuric acid (5 mL) at 0° C. The reaction was stirred at 0° C. for 3hours (TLC control) and then diluted with water (20 mL) and extractedwith diethyl ether (3×25 mL). The combined extract was washed with water(2×10 mL), brine, dried over anhydrous MgSO₄, filtered and concentratedin vacuo to afford crudemethyl-2-bromo-3-(4′-dibenzofuran-4-ylbiphen-4-ylmethylsulfanyl)-2-(4-trifluoromethylbenzyl-amino)propionate,which was used immediately without purification.

[0384] To the bromide (prepared in the previous step) in anhydrousdimethylformamide (5 mL) was added 4-trifuoromethylbenzylamine (80 mg,0.45 mmol) and triethylamine (0.5 mL). The reaction was stirred at roomtemperature for 16 hours and then poured into water, and extracted withdiethyl ether (3×25 mL). The combined extract was washed with water(2×10 mL), brine, dried over anhydrous MgSO₄, filtered and concentratedin vacuo to affordmethyl-3-(4′-dibenzofuran-4-ylbiphen-4-ylmethylsulfanyl)-2-(4-trifluoromethylbenzyl-amino)-propionate.

[0385] 2N Sodium hydroxide (0.5 mL) was added to a stirred solution ofthe amino methyl ester in a mixture of tetrahydrofuran (5 mL) andmethanol (1 mL). The solution was stirred for 1 hour and then acidifiedto pH 4 with 2N hydrochloric acid. The reaction mixture was extractedwith ethyl acetate (3×20 mL). The combined extract was washed withwater, brine, dried over anhydrous MgSO₄, filtered and concentrated invacuo. Purification of the product by flash column chromatography, using20% methanol in methylene chloride as eluent, afforded the titlecompound as a white solid. Rf: 0.40 (20% methanol in dichloromethane);¹H NMR (CDCl₃, 300 MHz) δ 7.87 (3H, m, Ar—H), 7.57 (3H, m, Ar—H), 7.56(2H, d, J=9 Hz, Ar—H), 7.31-7.41 (6H, m, Ar—H), 7.29 (2H, t, J=9 Hz,Ar—H), 7.19 (3H, m, Ar—H), 3.98 (2H, s, PhCH₂S), 3.70 (3H, m,CHN+PhCH₂N), 3.09 (1H, m CHHCHN), 2.89 (1H, m, CHHCHN); ESI-LCMS e/zcalcd for C₃₆H₂₈F₃NO₃S 611.681, found 613 (M+H)⁺.

Example 61

[0386] Trifluoro-methanesulfonic acid4-(2-benzyl-benzofuran-3-yl)-phenyl ester.

[0387] To a stirred solution of the known phenol,4-(2-benzylbenzofuran-3-yl)-phenol, (7.2 g, 24 mmol) in anhydrousmethylene chloride (100 mL), was added triethylamine (4.86 g, 6.7 mL, 48mmol) and then N-phenyltrifluoromethanesulfonimide (9.4 g, 26.4 mmol)portionwise as a solid. The resulting solution was stirred for 2 hoursat room temperature and then diluted with water, extracted with diethylether (3×100 mL). The combined extract was washed with water, brine,dried over anhydrous MgSO₄, filtered and concentrated in vacuo.Purification of the product by flash column chromatography, using 10%ethyl acetate in heptane as eluent, afforded the title compound as awhite solid (9.35 g, 90%).

Example 62

[0388] 4′-(2-Benzylbenzofuran-3-yl)biphenyl-4-carbaldehyde.

[0389] To a stirred solution of the triflate (from Example 61) (9.35 g,21.6 mmol) and tetrakis-(triphenylphosphine)palladium(0) (750 mg, 0.65mmol) in toluene (70 mL) was added a solution of 4-formylphenylboronicacid (4.06 g, 27.05 mmol) in ethanol (20 mL) and 2N sodium carbonate(21.6 mL, 43.2 mmol). The resulting suspension was stirred at 100° C.for 4 hrs (TLC control). The reaction was cooled, diluted with water (50mL) and extracted with diethyl ether (3×100 mL). The combined extractwas washed with water, brine, dried over anhydrous MgSO₄, filtered andconcentrated in vacuo.

[0390] The resulting brown solid was redissolved in tetrahydrofuran (50mL). 2N Hydrochloric acid (10 mL) was added and the resulting solutionwas stirred at room temperature for 1 hour, and then diluted with water(50 mL) and extracted with diethyl ether (3×100 mL). The combinedextract was washed with water, brine, dried over anhydrous MgSO₄,filtered and concentrated in vacuo. Purification of the product by flashcolumn chromatography, using 20% ethyl acetate in heptane as eluent,afforded the title compound as a white solid (7.34 g, 88%).

Example 63

[0391] 4′-(2-Benzylbenzofuran-3-yl)biphenyl-4-methanol

[0392] To a solution of4′-(2-benzylbenzofuran-3-yl)biphenyl-4-carbaldehyde (5.0 g, 12.9 mmol)in ethanol (100 mL) and tetrahydrofuran (25 mL) was added sodiumborohydride (980 mg, 25.8 mmol) as a solid in 3 portions. The reactionwas stirred at room temperature for 1 hour (TLC control) and then pouredinto water (100 mL) and extracted with diethyl ether (3×100 mL). Thecombined extract was washed with water, brine, dried over anhydrousMgSO₄, filtered and concentrated in vacuo to afford the title compoundas a white solid (5.02 g, 99%).

Example 64

[0393] 2-Benzyl-3-(4′-bromomethylbiphen-4-yl)benzofuran

[0394] To a solution of 4′-(2-benzylbenzofuran-3-yl)biphenyl-4-methanol(5.01 g, 12.7 mmol) in anhydrous acetonitrile (75 mL) was addeddibromotriphenylphosphorane (5.45 g, 12.7 mmol) as a solid portionwiseover 15 mins. The reaction was stirred for 2 hours (TLC control) andthen poured into water (100 mL) and extracted with diethyl ether (3×100mL). The combined extract was washed with water, brine, dried overanhydrous MgSO₄, filtered and concentrated in vacuo to afford the titlecompound as an off-white solid (4.98 g, 87%): ¹H NMR (CDCl₃, 300 MHz): δ7.70 (2H, m, Ar—H), 7.63 (4H, m, Ar—H), 7.50 (3H, m, Ar—H), 7.30 (4H, m,Ar—H), 7.25 (4H, m, Ar—H), 4.57 (2H, s, CH₂Br), 4.26 (2H, PhCH₂).

Example 65

[0395](2R)-Methyl-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-2-tert-butoxycarbonylaminopropionate.

[0396] N-Boc-L-Cysteine methyl ester (260 mg, 0.23 mL, 1.1 mmol) wasadded dropwise to a stirred suspension of2-Benzyl-3-(4′-bromomethylbiphen-4-yl)benzofuran (500 mg, 1.1 mmol) andcesium carbonate (720 mg, 2.21 mmol) in anhydrous dimethylformamide (20mL). The reaction was stirred at room temperature for 2 hrs (TLCcontrol) and then poured into water (100 mL) and extracted with diethylether (3×100 mL). The combined extract was washed with water, brine(3×), dried over anhydrous MgSO₄, filtered and concentrated in vacuo.Purification using 30% ethyl acetate in heptane as eluent afforded thetitle compound as a white solid (620 mg, 92%): ¹H NMR (CDCl₃, 300 MHz):δ 7.70 (2H, m, Ar—H), 7.64 (2H, m, Ar—H), 7.60 (3H, m, Ar—H), 7.48 (1H,m, Ar—H), 7.42 (2H, m, Ar—H), 7.26-7.36 (7H, m, Ar—H), 5.32 (1H, d, J=8Hz, NH), 4.58 (1H, m, CHN), 4.26 (2H, PhCH₂), 3.79 (2H, s, PhCH2S), 3.76(3H, s, OMe), 2.95 (1H, dd, J=13, 5 Hz, CHHCHN), 2.84 (1H, dd, J=13, 7Hz, CHHCHN), 1.46 (9H, s, CMe₃); ESI-LCMS e/z calcd for C₃₇H₃₇NO₅S607.760, found 608 (M+H)⁺, 630 (M+Na)⁺.

Example 66

[0397](2R)-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-2-tert-butoxy-carbonylamino-propionicacid.

[0398] 1N Sodium hydroxide (2 mL) was added to a stirred solution of(2R)-methyl-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-2-tert-butoxycarbonylamino-propionate(100 mg) in a mixture of tetrahydrofuran (6 mL) and methanol (2 mL). Thesolution was stirred for 1 hour and then acidified to pH 3 with 1Nhydrochloric acid. The reaction mixture was extracted with ethyl acetate(3×10 mL). The combined extract was washed with water, brine, dried overanhydrous MgSO₄, filtered and concentrated in vacuo. Purification of theproduct by flash column chromatography, using 5% methanol in methylenechloride as eluent, afforded the title compound as a white solid (82 mg,84%): mp. 89-90° C. Rf=0.50 (10% methanol in dichloromethane). ¹H NMR(DMSO-d6, 300 MHz) δ 7.8 (2H, d, J=9 Hz, Ar—H), 7.6 (6H, m, Ar—H), 7.4(2H, d, J=9 Hz, Ar—H), 7.28 (5H, m, Ar—H), 7.21 (2H, d, J=8 Hz, Ar—H),6.42 (1H, d, J=8 Hz, NH), 4.26 (2H, s, PhCH2), 3.95 (1H, m, CHN), 3.75(2H, s, PhCH2S), 2.9 (1H, dd, J=15, 5 Hz, CHHCHN), 2.74 (1H, dd, J=15, 8Hz, CHHCHN), 1.39 (9H, s, tBu); ESI-LCMS e/z calcd for C₃₆H₃₅NO₅S593.74, found 617 (M+Na)⁺.

Example 67

[0399] (2R,4RS)-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfinyl]-2-tert-butoxycarbonylaminopropionicacid.

[0400] Sodium perborate tetrahydrate (18.3 mg, 0.12 mmol) was added as asolid to a stirred solution of(2R)-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-2-tert-butoxycarbonylamino-propionicacid (70 mg, 0.12 mmol) in acetic acid (3 mL) at 40° C. This solutionwas stirred at 40° C. for 1 hour (HPLC control) and then diluted withethyl acetate (50 mL), washed with water, brine (2×), dried overanhydrous MgSO₄, filtered and concentrated in vacuo. Purification bytrituration of the product with diethyl ether afforded the titlecompound as a 1:1 mix of diastereoisomers as a white solid (68 mg, 93%):mp. 195-196° C. Rf 0.15 (20% methanol in dichloromethane). ¹H NMR(DMSO-d6, 300 MHz) δ 7.82 (2H, m, Ar—H), 7.56-7.80 (6H, m, Ar—H), 7.4(2H, d, m, Ar—H), 7.34-7.18 (7H, m, Ar—H), 6.42 (1H, br s, NH), 4.26(2H, s, PhCH2), 4.20 (1H, m), 3.90 (2H, m, PhCH ₂S), 2.9 (2H, m CHHCHN),1.40 (9H, s, tBu); ESI-LCMS e/z calcd for C₃₆H₃₅NO₆S 609.730, found 610(M+H)⁺.

Example 68

[0401](2R)-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfonyl]-2-tert-butoxycarbonylaminopropionicAcid.

[0402] Sodium perborate tetrahydrate (320 mg, 2.1 mmol) was added as asolid to a stirred solution of(2R)-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-2-tert-butoxycarbonylamino-propionicacid (440 mg, 0.74 mmol) in acetic acid (10 mL) at 40° C. This solutionwas stirred at 40° C. for 2 hours (HPLC control) and then diluted withethyl acetate (50 mL), washed with water, brine (2×), dried overanhydrous MgSO₄, filtered and concentrated in vacuo. Purification of theproduct by flash column chromatography, using 15% methanol in methylenechloride as eluent, afforded the title compound as a white solid (426mg, 92%): mp. 202-203° C. Rf 0.40 (20% methanol in dichloromethane). ¹HNMR (DMSO-d6, 300 MHz) δ 7.84 (2H, d, J=9 Hz, Ar—H), 7.74 (2H, d, J=9Hz, Ar—H), 7.60 (4H, m, Ar—H), 7.48 (2H, d, J=9 Hz, Ar—H), 7.29 (5H, m,Ar—H), 7.22 (2H, d, J=8 Hz, Ar—H), 6.58 (1H, br s, NH), 4.51 (2H, s,PhCH2), 4.27 (2H, s, PhCH2S), 4.16 (1H, m, CHN), 3.56 (1H, dd, J=15, 5Hz, CHHCHN), 3.20 (1H, dd, J=15, 8 Hz, CHHCHN), 1.37 (9H, s, tBu);ESI-LCMS e/z calcd for C₃₆H₃₅NO₇S 625.739, found 626 (M+H)⁺.

Example 69

[0403](2R)-Methyl-2-Amino-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-2-propionate.

[0404] TMSI (0.41 g, 0.29 mL, 2.06 mmol) was added dropwise to a stirredsolution of(2R)-Methyl-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-2-tert-butoxy-carbonylamino-propionate(1.0 g, 1.64 mmol) in anhydrous methylene chloride (10 mL). The reactionwas stirred for 30 mins. and then poured into 1N sodium bicarbonatesolution (10 mL), extracted with ethyl acetate (3×10 mL). The combinedextract was washed with water, brine, dried over anhydrous MgSO₄,filtered and concentrated in vacuo. Purification of the product by flashcolumn chromatography, using 5% methanol in methylene chloride aseluent, afforded the title compound as a pale yellow oil (790 mg, 95%).Rf=0.50 (5% methanol in dichloromethane). ¹H NMR (DMSO-d6, 300 MHz) δ7.7 (2H, m, Ar—H), 7.62 (5H, m, Ar—H), 7.44 (4H, m, Ar—H), 7.28 (6H, m,Ar—H), 4.26 (2H, s, PhCH₂), 3.80 (2H, s, PhCH ₂S), 3.74 (3H, s, OMe),3.65 (1H, dd, J=7.5, 5 Hz, CHN), 2.89 (1H, dd, J=15, 5 Hz, CHHCHN), 2.73(1H, dd, J=15, 7.5 Hz, CHHCHN); ESI-LCMS e/z calcd for C₃₂H₂₉NO₃S507.65, found 509 (M+H)⁺.

Example 70

[0405](2R)-2-Benzoylamino-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-propionicacid.

[0406](2R)-2-Benzoylamino-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-propionicacid was prepared according to the method described in Example 35,Method A, using benzoic acid as the corresponding carboxylic acid. Thetitle compound was isolated as a white solid: mp. 138-139° C. Rf=0.25(10% methanol in dichloromethane). ¹H NMR (CDCl₃, 300 MHz) δ 7.74 (2H,d, J=9 Hz, Ar—H), 7.48-7.62 (6H, m, Ar—H), 7.30-7.42 (6H, m, Ar—H), 7.22(8H, m, Ar—H), 6.90 (1H, d, J=8 Hz, NH), 4.88 (1H, d, J=8 Hz, CHN), 4.18(2H, s, PhCH₂), 3.76 (2H, s, PhCH₂S), 3.06 (2H, d, J=8 Hz, CH ₂CHN);ESI-LCMS e/z calcd for C₃₈H₃₁NO₄S 597.732, found 599 (M+H)⁺.

Example 71

[0407](2R)-2-Phenylacetylamino-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethyl-sulfanyl]-propionicAcid.

[0408](2R)-2-Phenylacetylamino-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-propionicacid was prepared according to the method described in Example 35,Method A, using phenylacetic acid as the corresponding carboxylic acid.The title compound was isolated as a white solid: mp. 77-78° C. Rf=0.25(10% methanol in dichloromethane). ¹H NMR (CDCl₃, 300 MHz) δ 7.56-7.72(7H, m, Ar—H), 7.48 (1H, m, Ar—H), 7.20-7.40 (14H, m, Ar—H), 6.29 (1H,d, J=7 Hz, NH), 4.77 (1H, dd, J=13, 6 Hz, CHN), 4.25 (2H, s, PhCH₂),3.66 (2H, s, PhCH ₂CO), 3.62 (2H, s, PhCH₂S), 2.92 (2H, m, CH ₂CHN);ESI-LCMS e/z calcd for C₃₉H₃₃NO₄S 611.759, found 613 (M+H)⁺.

Example 72

[0409](2R)-2-{3-Phenylpropionoylamino-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]}-propionicAcid.

[0410](2R)-2-{3-Phenylpropionoylamino-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]}-propionicacid was prepared according to the method described in Example 35,Method A, using 3-phenylpropionic acid as the corresponding carboxylicacid. The title compound was isolated as a white solid: mp. 158-159° C.Rf=0.28 (10% methanol in dichloromethane). ¹H NMR (CDCl₃, 300 MHz) δ7.58-7.66 (7H, m, Ar—H), 7.48 (1H, m, Ar—H), 7.38 (2H, m, Ar—H),7.12-7.23 (12H, m, Ar—H), 6.16 (1H, d, J=8 Hz, NH), 4.76 (1H, dd, J=13,6 Hz, CHN), 4.26 (2H, s, PhCH₂), 3.74 (2H, s, PhCH₂S), 2.94 (4H, m, CH₂CHN+CH ₂CH₂CO) 2.52 (2H, m, CH₂CH ₂CO); ESI-LCMS e/z calcd forC₄₀H₃₅NO₄S 625.786, found 626 (M+H)⁺.

Example 73

[0411](2R)-2-[{3H-Benzoimidazole-5-carbonyl)amino]-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]}-propionicAcid.

[0412](2R)-2-[(3H-Benzoimidazole-5-carbonyl)amino]-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]}-propionicacid was prepared according to the method described in Example 35,Method A, using 3H-benzimidazole-5-carboxylic acid as the correspondingcarboxylic acid. The title compound was isolated as an off-white solid:mp. 149-150° C. Rf=0.35 (15% methanol in dichloromethane). ¹H NMR(DMSO-d6, 300 MHz) δ 8.76 (1H, d, J=8 Hz, NH), 8.36 (1H, s, CHN(═N)),8.20 (1H, br s, NH), 7.76-7.82 (3H, m, Ar—H), 7.54-7.72 (8H, m, Ar—H),7.42 (2H, d, J=8 Hz, Ar—H), 7.20-7.35 (7H, m, Ar—H), 4.65 (1H, m, CHN),4.26 (2H, s, PhCH₂), 3.84 (2H, s, PhCH₂S), 2.94 (2H, m, CH ₂CHN);ESI-LCMS e/z calcd for C₃₉H₃₁N₃O₄S 637.757, found 638 (M+H)⁺.

Example 74

[0413](2R)-2-(4-Fluorophenylacetylamino)-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-propionicAcid.

[0414](2R)-2-(4-Fluorophenylacetylamino)-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-propionicacid was prepared according to the method described in Example 35,Method A, using 4-fluorophenylacetic acid as the correspondingcarboxylic acid. The title compound was isolated as a white solid: mp.82-84° C. Rf=0.15 (10% methanol in dichloromethane). ¹H NMR (CDCl₃, 300MHz) δ 7.48-7.62 (7H, m, Ar—H), 7.42 (1H, d, J=8 Hz, Ar—H), 7.12-7.28(11H, m, Ar—H), 6.94 (3H, m, Ar—H), 6.24 (1H, d, J=7 Hz, NH), 4.70 (1H,dd, J=13, 6 Hz, CHN), 4.18 (2H, s, PhCH₂), 3.62 (2H, s, PhCH ₂CO), 3.50(2H, s, PhCH ₂S), 2.84 (2H, m, CH ₂CHN); ESI-LCMS e/z calcd forC₃₉H₃₂FNO₄S 629.749, found 630 (M+H)⁺.

Example 75

[0415](2R)-2-(3-Nitrophenylacetylamino)-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-propionicAcid.

[0416](2R)-2-(3-Nitrophenylacetylamino)-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-propionicacid was prepared according to the method described in Example 35,Method A, using 3-nitrophenylacetic acid as the corresponding carboxylicacid. The title compound was isolated as an off-white solid: mp.108-109° C. Rf=0.10 (10% methanol in dichloromethane). ¹H NMR (CDCl₃,300 MHz) δ 8.17 (1H, t, J=3 Hz, Ar—H), 8.12 (1H, dd, J=8, 3 Hz, Ar—H),7.68 (2H, d, J=8 Hz, Ar—H), 7.56-7.62 (6H, m, Ar—H), 7.48 (2H, m, Ar—H),7.36 (2H, d, J=8 Hz, Ar—H), 7.24-7.32 (7H, m, Ar—H), 6.36 (1H, d, J=7Hz, NH), 4.80 (1H, dd, J=13, 6 Hz, CHN), 4.24 (2H, s, PhCH₂), 3.74 (2H,s, PhCH ₂CO), 3.66 (2H, s, PhCH ₂S), 2.90 (2H, d, J=6 Hz, CH ₂CHN);ESI-LCMS e/z calcd for C₃₉H₃₂N₂O₆S 656.756, found 657 (M+H)⁺.

Example 76

[0417](2R)-2-[(1H-Indole-5-carbonyl)amino]-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]}-propionicAcid.

[0418](2R)-2-[(1H-Indole-5-carbonyl)amino]-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]}-propionicacid was prepared according to the method described in Example 35,Method A, using 1H-indole-5-carboxylic acid as the correspondingcarboxylic acid. The title compound was isolated as a white solid: mp.181-182° C. Rf=0.40 (20% methanol in dichloromethane). ¹H NMR (DMSO-d6,300 MHz) δ 11.36 (2H, br s, OH, NH), 8.16 (2H, s, Ar—H), 7.78 (2H, d,J=8 Hz, Ar—H), 7.54-7.66 (7H, m, Ar—H), 7.40 (4H, m, Ar—H), 7.18-7.36(6H, m, Ar—H), 6.54 (1H, br s, Ar—H), 4.45 (1H, m, CHN), 4.26 (2H, s,PhCH₂), 3.78 (2H, dd, J=15, 13 Hz, PhCH₂S), 3.04 (1H, dd, J=13, 5 Hz,CHHCHN) 2.95 (1H, dd, J=13, 7 Hz, CHHCHN); ESI-LCMS e/z calcd forC₄₀H₃₂N₂O₄S 636.769, found 638 (M+H)⁺.

Example 77

[0419](2R)-2-(4-Nitrophenylacetylamino)-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-propionicacid.

[0420](2R)-2-(4-Nitrophenylacetylamino)-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-propionicacid was prepared according to the method described in Example 35,Method A, using 4-nitrophenylacetic acid as the corresponding carboxylicacid. The title compound was isolated as an off-white solid: mp.102-103° C. Rf=0.70 (20% methanol in dichloromethane). ¹H NMR (DMSO-d6,300 MHz) δ 8.68 (1H, d, J=8 Hz, NH), 8.16 (2H, d, J=9 Hz, Ar—H), 7.82(2H, d, J=8 Hz, Ar—H), 7.64 (5H, m, Ar—H), 7.56 (3H, m, Ar—H), 7.31 (6H,m, Ar—H), 7.24 (3H, m, Ar—H), 4.46 (1H, ddd, J=13, 8, 5 Hz, CHN), 4.26(2H, s, PhCH₂), 3.77 (2H, s, PhCH ₂CO), 3.68 (2H, s, PhCH ₂S), 2.82 (1H,dd, J=13, 5 Hz, CHHCHN), 2.70 (1H, dd, J=13, 8 Hz, CHHCHN); ESI-LCMS e/zcalcd for C₃₉H₃₂N₂O₆S 656.756, found 657 (M+H)⁺.

Example 78

[0421](2R)-2-(2-Nitrophenylacetylamino)-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-propionicAcid.

[0422](2R)-2-(2-Nitrophenylacetylamino)-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-propionicacid was prepared according to the method described in Example 35,Method A, using 2-nitrophenylacetic acid as the corresponding carboxylicacid. The title compound was isolated as an off-white solid: mp.189-191° C. Rf=0.72 (20% methanol in dichloromethane). ¹H NMR (DMSO-d6,300 MHz) δ 8.16 (1H, d, J=8 Hz, NH), 7.97 (1H, d, J=8 Hz, Ar—H), 7.82(2H, d, J=8 Hz, Ar—H), 7.64 (65H, m, Ar—H), 7.52 (3H, m, Ar—H), 7.38(2H, d, J=9 Hz, Ar—H), 7.30 (4H, m, Ar—H), 7.24 (3H, m, Ar—H), 4.30 (3H,m, CHN+PhCH₂), 3.96 (2H, s, PhCH ₂CO), 3.68 (2H, dd, J=16, 12 Hz, PhCH₂S), 2.85 (1H, dd, J=16, 5 Hz, CHHCHN), 2.70 (1H, dd, J=16, 7 Hz,CHHCHN); ESI-LCMS e/z calcd for C₃₉H₃₂N₂O₆S 656.756, found 657 (M+H)⁺.

Example 79

[0423](2R)-2-(4-Hydroxyphenylacetylamino)-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-propionicacid.

[0424](2R)-2-(4-Hydroxyphenylacetylamino)-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-propionicacid was prepared according to the method described in Example 35,Method A, using 4-hydroxyphenylacetic acid as the correspondingcarboxylic acid. The title compound was isolated as a white solid: mp.148-149° C. Rf=0.60 (20% methanol in dichloromethane). ¹H NMR (DMSO-d6,300 MHz) δ 9.30 (1H, br s, OH), 7.82 (2H, d, J=8 Hz, Ar—H), 7.70 (1H, d,J=8 Hz, NH), 7.62 (5H, m, Ar—H), 7.56 (1H, d, J=7 Hz, Ar—H), 7.30 (6H,m, Ar—H), 7.22 (3H, m, Ar—H), 7.18 (2H, d, J=8 Hz, Ar—H), 6.67 (1H, d,J=8 Hz, Ar—H), 4.26 (2H, s, PhCH₂), 4.18 (1H, m, CHN), 3.73 (2H, d, J=13Hz, PhCHHCO), 3.66 (1H, d, J=13 Hz, PhCHHCO), 3.38 (2H, m, PhCH ₂S),2.88 (1H, dd, J=13, 5 Hz, CHHCHN), 2.76 (1H, dd, J=13, 7 Hz, CHHCHN);ESI-LCMS e/z calcd for C₃₉H₃₃NO₅S 627.758, found 628 (M+H)⁺.

Example 80

[0425](2R)-2-Acetylamino-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-propionicAcid.

[0426](2R)-2-Acetylamino-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-propionicacid was prepared according to the method described in Example 35,Method B, using acetyl chloride as the corresponding acylating reagent.The title compound was isolated as a white solid: mp. 131-132° C.Rf=0.60 (20% methanol in dichloromethane). ¹H NMR (DMSO-d6, 300 MHz) δ7.82 (2H, d, J=9 Hz, Ar—H), 7.64 (5H, m, Ar—H), 7.56 (1H, d, J=8 Hz,NH), 7.40 (2H, m, Ar—H), 7.31 (5H, m, Ar—H), 7.24 (3H, m, Ar—H), 4.26(3H, m, CHN+PhCH₂), 3.77 (2H, s, PhCH ₂S), 2.82 (1H, dd, J=13, 5 Hz,CHHCHN), 2.69 (1H, dd, J=13, 8 Hz, CHHCHN), 1.85 (3H, s, CH ₃CO);ESI-LCMS e/z calcd for C₃₃H₂₉NO₄S 536.661, found 537 (M+H)⁺.

Example 81

[0427](2R)-2-(4-Methoxyphenylacetylamino)-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-propionicAcid.

[0428](2R)-2-(4-Methoxyphenylacetylamino)-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-propionicacid was prepared according to the method described in Example 35,Method A, using 4-methoxyphenylacetic acid as the correspondingcarboxylic acid. The title compound was isolated as a white solid: mp.59-60° C. Rf=0.75 (20% methanol in dichloromethane). ¹H NMR (DMSO-d6,300 MHz) δ 8.40 (1H, d, J=8 Hz, NH), 7.84 (2H, d, J=8 Hz, Ar—H), 7.64(5H, m, Ar—H), 7.30 (5H, m, Ar—H), 7.20 (5H, m, Ar—H), 6.84 (3H, m,Ar—H), 4.42 (1H, m, CHN), 4.27 (2H, s, PhCH₂), 3.76 (2H, s, PhCH ₂CO),3.71 (2H, s, PhCH ₂S), 3.68 (3H, s, OMe), 2.84 (1H, dd, J=13, 5 Hz,CHHCHN), 2.68 (1H, dd, J=13, 7 Hz, CHHCHN); ESI-LCMS e/z calcd forC₄₀H₃₅NO₅S 641.784, found 643 (M+H)⁺.

Example 82

[0429](2R)-2-(4-Aminophenylacetylamino)-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-propionicAcid.

[0430](2R)-2-(4-Aminophenylacetylamino)-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-propionicacid was prepared according to the method described in Example 35,Method A, using 4-aminophenylacetic acid as the corresponding carboxylicacid. The title compound was isolated as a pale yellow solid: mp.170-172° C. Rf=0.50 (20% methanol in dichloromethane). ¹H NMR (DMSO-d6,300 MHz) δ 7.81 (2H, d, J=8 Hz, Ar—H), 7.64 (6H, m, Ar—H), 7.52 (1H, m,NH), 7.30 (7H, m, Ar—H), 7.21 (2H, d, J=8 Hz, Ar—H), 6.84 (2H, d, J=8Hz, Ar—H), 6.48 (2H, d, J=8 Hz, Ar—H), 4.26 (2H, s, PhCH₂), 4.16 (1H, m,CHN), 3.72 (1H, d, J=13 Hz, PhCHHCO), 3.68 (1H, d, J=13 Hz, PhCHHCO),3.28 (2H, s, PhCH ₂S), 2.89 (1H, dd, J=13, 5 Hz, CHHCHN), 2.76 (1H, dd,J=13, 7 Hz, CHHCHN); ESI-LCMS e/z calcd for C₃₉H₃₄N₂O₄S 626.774, found627 (M+H)⁺.

Example 83

[0431](2R)-3-[4′-(2-Benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-2-methoxy-carbonylaminopropionicAcid.

[0432](2R)-3-[4′-(2-Benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-2-methoxycarbonyl-aminopropionicacid was prepared according to the method described in Example 35,Method B, using methyl chloroformate as the corresponding acylatingreagent. The title compound was isolated as a white solid: Rf=0.20 (10%methanol in dichloromethane). ¹H NMR (DMSO-d6, 300 MHz) δ 7.84 (2H, d,J=9 Hz, Ar—H), 7.68 (2H, d, J=9 Hz, Ar—H), 7.60 (5H, m, Ar—H), 7.41 (2H,d, J=9 Hz, Ar—H), 7.26 (5H, m, Ar—H, NH), 7.20 (2H, d, J=8 Hz, Ar—H),4.28 (2H, s, PhCH2), 4.18 (1H, m, CHN), 3.79 (2H, s, PhCH2S), 3.55 (3H,s, OMe), 2.86 (1H, dd, J=13, 5 Hz, CHHCHN), 2.69 (1H, dd, J=13, 8 Hz,CHHCHN); ESI-LCMS e/z calcd for C₃₃H₂₉NO₅S 551.660, found 551: M+.

Example 84

[0433](2R)-3-[4′-(2-Benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-2-isobutoxy-carbonylaminopropionicacid.

[0434](2R)-3-[4′-(2-Benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-2-isobutoxy-carbonylaminopropionicacid was prepared according to the method described in Example 35,Method B, using isobutyl chloroformate as the corresponding acylatingreagent. The title compound was isolated as a pale yellow solid: Rf=0.30(10% methanol in dichloromethane). ¹H NMR (DMSO-d6, 300 MHz) δ 7.82 (2H,d, J=9 Hz, Ar—H), 7.72 (2H, d, J=9 Hz, Ar—H), 7.64 (4H, m, Ar—H), 7.49(1H, d, J=8 Hz, NH), 7.40 (2H, d, J=9 Hz, Ar—H), 7.31 (5H, m, Ar—H),7.24 (2H, d, J=8 Hz, Ar—H), 4.26 (2H, s, PhCH2), 4.18 (1H, m, CHN), 3.79(2H, s, PhCH₂S), 3.66 (2H, m, OCH₂), 2.82 (1H, dd, J=13, 5 Hz, CHHCHN),2.71 (1H, dd, J=13, 8 Hz, CHHCHN), 1.84 (1H, m, CHMe₂), 0.87 (6H, d, J=7Hz); ESI-LCMS e/z calcd for C₃₆H₃₅NO₅S 593.740, found 617: (M+Na)⁺.

Example 85

[0435](2R)-3-[4′-(2-Benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-2-[(morpholine-4-carbonyl)amino]propionicAcid.

[0436](2R)-3-[4′-(2-Benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-2-[(morpholine-4-carbonyl)amino]propionicacid was prepared according to the method described in Example 35,Method B, using 4-morpholinylcarbonyl chloride as the correspondingacylating reagent. The title compound was isolated as an off-whitesolid: Rf=0.10 (10% methanol in dichloromethane). ¹H NMR (DMSO-d6, 300MHz) δ 7.84 (2H, d, J=9 Hz, Ar—H), 7.78 (2H, d, J=9 Hz, Ar—H), 7.64 (4H,m, Ar—H), 7.42 (2H, d, J=9 Hz, Ar—H), 7.32 (5H, m, Ar—H), 7.26 (2H, d,J=8 Hz, Ar—H), 6.82 (1H, d, J=8 Hz, NH), 4.30 (3H, m, PhCH₂+CHN), 3.79(2H, s, PhCH₂S), 3.52 (4H, m, CH ₂OCH ₂), 3.31 (4H, m, CH ₂NCH ₂), 2.82(1H, dd, J=13, 5 Hz, CHHCHN), 2.73 (1H, dd, J=13, 8 Hz, CHHCHN);ESI-LCMS e/z calcd for C₃₆H₃₄N₂O₅S 606.740, found 607: (M+H)⁺.

Example 86

[0437](2R)-3-[4′-(2-Benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-2-(3,3-dimethyl-ureido)-propionicAcid.

[0438](2R)-3-[4′-(2-Benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-2-(3,3-dimethyl-ureido)-propionicacid was prepared according to the method described in Example 35,Method B, using N,N-Dimethylcarbamoyl chloride as the correspondingacylating reagent. The title compound was isolated as a pale yellow waxysolid: Rf=0.10 (10% methanol in dichloromethane). ¹H NMR (DMSO-d6, 300MHz) δ 7.83 (2H, d, J=9 Hz, Ar—H), 7.76 (2H, m, Ar—H), 7.62 (4H, m,Ar—H), 7.42 (2H, d, m, Ar—H), 7.30 (4H, m, Ar—H), 7.22 (3H, d, J=8 Hz,Ar—H), 6.48 (1H, d, J=8 Hz, NH), 4.26 (3H, m, PhCH₂+CHN), 3.80 (2H, s,PhCH₂S), 3.18 (2H, m CH ₂CHN), 2.80 (6H, s, NMe₂) ESI-LCMS e/z calcd forC₃₄H₃₂N₂O₄S 564.703, found 565 (M+H)⁺.

Example 87

[0439](2R)-3-[4′-(2-Benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-2-benzyloxy-carbonylaminopropionicAcid.

[0440](2R)-3-[4′-(2-Benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-2-benzyloxy-carbonylaminopropionicacid was prepared according to the method described in Example 35,Method B, using benzyl chloroformate as the corresponding acylatingreagent. The title compound was isolated as an off-white solid: Rf=0.20(10% methanol in dichloromethane). ¹H NMR (DMSO-d6, 300 MHz) δ 7.84 (2H,d, J=9 Hz, Ar—H), 7.58-7.75 (6H, m, Ar—H, NH), 7.40 (2H, d, J=8 Hz,Ar—H), 7.26-7.36 (10H, m, Ar—H), 7.24 (3H, d, J=8 Hz, Ar—H), 5.06 (2H,s, OCH ₂), 4.26 (2H, s, PhCH₂), 4.18 (1H, m, CHN), 3.82 (2H, s, PhCH₂S),2.85 (1H, dd, J=13, 5 Hz, CHHCHN), 2.73 (1H, dd, J=13, 8 Hz, CHHCHN);ESI-LCMS e/z calcd for C₃₉H₃₃NO₅S 627.758, found 628: (M+H)⁺.

Example 88

[0441](2R)-3-[4′-(2-Benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-2-(4-methyl-3-nitrobenzenesulfonylamino)-propionicAcid.

[0442](2R)-3-[4′-(2-Benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-2-(4-methyl-3-nitrobenzenesulfonylamino)-propionicacid was prepared according to the method described in Example 35,Method B, using 4-methyl-3-nitrobenzenesulfonyl chloride as thecorresponding acylating reagent. The title compound was isolated as awhite solid: Rf=0.45 (10% methanol in dichloromethane). ¹H NMR (CDCl₃,300 MHz) δ 8.56 (1H, s, Ar—H), 7.99 (1H, d, J=9 Hz, Ar—H), 7.58-7.75(7H, m, Ar—H), 7.42 (2H, m, Ar—H), 7.36 (2H, m, Ar—H), 7.21-7.36 (7H, m,Ar—H), 4.21 (3H, m, PhCH₂+CHN), 3.82 (2H, s, PhCH₂S), 2.95 (2H, m,CH₂CHN), 2.42 (3H, s, Me); ESI-LCMS e/z calcd for C₃₈H₃₂N₂O₇S₂ 692.810,found 693 (M+H)⁺.

Example 89

[0443] 2-Chloro-4,6-diphenylpyrimidine.

[0444] A mixture of 2,4,6-trichloropyrimidine, 2.76 g (15.0 mmol),phenylboronic acid, 3.66 g (30.0 mmol), Pd(OAc)₂, 86 mg (0.38 mmol),triphenylphosphine, 200 mg (0.76 mmol) in 150 mL of ethylene glycoldimethyl ether was heated to obtain a clear solution. To the solutionwas added 25 mL of 4.0M aq. Na₂CO₃. The reaction mixture was refluxedfor 24 h at 70° C. The mixture was cooled to room temperature anddiluted with 100 mL ethyl acetate. The organic layer was washed withwater, sat. aq. NaCl, and dried (MgSO₄). After the solution wasconcentrated, the residue was recrystallized with Et₂O-Heptane (1:3) toafford the desired product in 1.64 g (41%) as a pale yellow solid. ¹HNMR (CDCl₃) 8.15-8.12 (m, 4H), 8.02 (s, 1H), 7.57-7.51 (m, 6H).

Example 90

[0445] [4-(4,6-Diphenylpyrimidin-2-yl)-phenyl]methanol.

[0446] A mixture of 2-chloro-4,6-diphenylpryimidine, 0.79 g (2.96 mmol),4-(hydroxylmethyl)phenylboronic acid, 0.45 g (2.96 mmol), Pd(PPh₃)₄, 342mg (0.296 mmol), in 2 mL of toluene and 1 mL of methanol was heated toobtain a clear solution. To the solution was added 2 mL of 4.0M aq.Na₂CO₃. The reaction mixture refluxed for 16 h at 70° C. The mixture wascooled to room temperature and diluted with 100 mL ethyl acetate. Theorganic layer was washed with water, sat. aq. NaCl, and dried (MgSO₄).After the solution was concentrated, the residue was recrystallized withEt₂O-Heptane (1:1) to afford the desired product in 0.38 g (38%) as ayellow solid. ¹H NMR (DMSO-d6) 8.72 (d, 2H, J=9.0 Hz), 8.52-8.47 (m,4H), 8.45 (s, 1H), 7.64-7.57 (m, 8H), 4.78 (d, 2H, J=6.7 Hz), 4.37 (t,1H, J=6.7 Hz).

Example 91

[0447] Methanesulfonic acid 4-(4,6-diphenylpyrimidin-2-yl)-benzyl ester.

[0448] A solution of [4-(4,6-diphenylpyrimidin-2-yl)-phenyl]methanol,0.38 g (1.11 mmol), triethylamine, 0.34 mL (2.45 mmol), and 6 mL ofmethylene chloride was cooled to 0° C. via ice-water bath.Methanesulfonyl chloride, 0.10 mL (1.23 mmol) was added dropwise over 5minutes. The solution stirred for 2 h at 0° C. The solution was quenchedwith 20 mL of water and diluted with 20 mL of ethyl acetate. The organiclayer was washed with water, sat. aq. NaCl, and dried (MgSO₄). After thesolution was concentrated, the residue was recrystallized withEtOAc-Heptane (1:2) to afford the desired product in 0.44 g (95%) as ayellow solid. ¹H NMR (DMSO-d6) 8.77 (d, 2H, J=9.0), 8.44-8.41 (m, 4H),8.30 (s, 1H), 7.68-7.61 (m, 8H), 5.37 (s, 2H), 3.11 (s, 3H)

Example 92

[0449] 2-tert-Butoxycarbonylamino-3-[4-(4,6-diphenylpyrimidin-2-yl)-benzylsulfanyl]propionicacid methyl ester.

[0450] A mixture of Methanesulfonic acid4-(4,6-diphenylpyrimidin-2-yl)-benzyl ester, 0.15 g (0.36 mmol),N-(tert-Butoxycarbonyl)-L-cysteine methyl ester, 0.08 mL (0.36 mmol),cesium carbonate, 235 mg (0.72 mmol), and 10 mL of N,N-dimethylformamidewas stirred at room temperature for 4 h. The mixture was diluted with 10mL of water and extracted with 2×50 mL of ethyl acetate. The organiclayer was washed with 2×50 mL portions of aq. LiCl, sat. aq. NaHCO₃,sat. aq. NaCl, and dried (MgSO₄). After the solution was concentrated,the residue was purified by column chromatography (eluted with 7%EtOAc-Heptane) to afford the desired product in 0.18 g (90%) as a whitesolid. ¹H NMR (CDCl₃) 8.67 (d, 2H, J=9.0 Hz), 8.30-8.27 (m, 4H), 8.02(s, 1H), 7.61-7.55 (m, 6H), 7.47 (d, 2H, J=9.0 Hz), 5.30 (d, 1H, J=7.7Hz), 4.63-4.52 (m, 1H), 3.82 (s, 2H), 3.76 (s, 3H), 2.93 (dd, 1H,J=15.7, 6.0 Hz), 2.84 (dd, 1H, J=15.7, 6.7 Hz), 1.47 (s, 9H).

Example 93

[0451] 2-tert-Butoxycarbonylamino-3-[4-(4,6-diphenylpyrimidin-2-yl)-benzylsulfanyl]propionicacid.

[0452] To a solution of 2-tert-Butoxycarbonylamino-3-[4-(4,6-diphenylpyrimidin-2-yl)-benzylsulfanyl]-propionicacid methyl ester, 0.18 g (0.32 mmol) in 10 mL of tetrahydrofuran and 5mL of methanol was added 1.62 mL of 1.0M aq. KOH. The solution wasstirred for 1 h at room temperature. The solution was diluted with 10 mLof water and acidified to pH 1-2. The aqueous was extracted with 3×30 mLportions of diethyl ether. The organic layers were combined, washed withsat. aq. NaHCO₃, sat. aq. NaCl, dried (MgSO₄). The solution wasconcentrated to the desired product in 0.10 g (57%) as an off-whitesolid. MP 250° C. decomp, Rf 0.09 (100% Ethyl Acetate); ¹H NMR (DMSO-d6)8.57 (d, 2H, J=9.3), 8.52-8.46b (m, 5H), 7.60-7.58 (m, 6H), 7.51 (d, 2H,J=9.3), 4.11 (m, 1H), 3.86 (s, 3H), 2.81 (dd, 1H, J=14.8, 5.0 Hz), 2.67(dd, 1H, J=15.3, 10.3), 1.39 (s, 9H). LCMS m/z calcd for C₃₁H₃₁N₃O₄S:541.2 found 542.6(M+1)

Example 94

[0453]2-Acetylmino-3-[4-(4,6-diphenylpyrimidin-2-yl)-benzylsulfanyl]-propionicAcid Methyl Ester.

[0454] A mixture of Methanesulfonic acid4-(4,6-diphenylpyrimidin-2-yl)-benzyl ester, 0.14 g (0.34 mmol),N-acetyl-L-cysteine methyl ester, 60 mg (0.346 mmol), cesium carbonate,219 mg (0.67 mmol), and 10 mL of N,N-dimethylformamide was stirred atroom temperature for 4 h. The mixture was diluted with 10 mL of waterand extracted with 2×50 mL of ethyl acetate. The organic layer waswashed with 2×50 mL portions of aq. LiCl, sat. aq. NaHCO₃, sat. aq.NaCl, and dried (MgSO₄). After the solution was concentrated, theresidue was purified by column chromatography (eluted with 7%EtOAc-Heptane) to afford the desired product in 90 mg (54%) as a paleyellow solid. ¹H NMR (CDCl₃) 8.67 (d, 2H, J=9.3 Hz), 8.30-8.25 (m, 4H),8.02 (s, 1H), 7.61-7.55 (m, 6H), 7.46 (d, 2H, J=9.3 Hz), 6.16 (d, 1H,7.7 Hz), 4.87-4.81 (m, 1H), 3.80 (s, 2H), 3.77 (s, 3H), 2.97 (dd, 1H,J=15.0, 5.3 Hz), 2.91 (dd, 1H, J=15.7, 6.3 Hz), 2.02 (s, 3H).

Example 95

[0455]2-Acetylamino-3-[4-(4,6-diphenyl-pyrimidin-2-yl)-benzylsulfanyl]-propionicAcid.

[0456] To a solution of2-acetylmino-3-[4-(4,6-diphenylpyrimidin-2-yl)-benzylsulfanyl]-propionicacid methyl ester, 90 mg (0.18 mmol) in 10 mL of tetrahydrofuran and 5mL of methanol was added 0.90 mL of 1.0M aq. KOH. The solution wasstirred for 1 h at room temperature. The solution was diluted with 10 mLof water and acidified to pH 1-2. The aqueous was extracted with 3×30 mLportions of diethyl ether. The organic layers were combined, washed withsat. aq. NaHCO₃, sat. aq. NaCl, dried (MgSO₄). The solution wasconcentrated to afford the desired product in 60 mg (69%) as a whitesolid. MP 223-226° C., Rf=0.07 (100% Ethyl Acetate); ¹H NMR (CDCl₃) 8.55(d, 2H, J=9.3), 8.20-8.15 (m, 4H), 7.93 (s, 1H), 7.52-7.45 (m, 6H), 7.40(d, 2H, J=9.3), 6.13 (d, 1H, J=8.0 Hz), 4.63 (q, 1H, J=13.3, 5.8 Hz),3.74 (s, 2H), 2.96 (dd, 1H, J=15.7, 6.0 Hz), 2.87 (dd, 1H, J=15.7, 6.3),1.94 (s, 3H). LCMS m/z calcd for C₂₈H₂₅N₃O₃S: 483.2 found 484.4(M+1)

Example 96

[0457] 4′-Bromo-biphenyl-4-carboxylic Acid Methyl Ester.

[0458] A mixture of methyl 4-iodobenzoate, 9.38 g (35.8 mmol),4-bromophenylboronic acid 7.18 g (35.8 mmol), Pd(PPh₃)₄, 2.07 g (1.79mmol), in 180 mL of toluene and 100 mL of ethanol was heated to obtain aclear solution. To the solution was added 30 mL of 4.0M aq. Na₂CO₃. Thereaction mixture refluxed for 4 h at 80° C. The mixture was cooled toroom temperature and diluted with 300 mL ethyl acetate. The organiclayer was washed with 2×300 mL portions of water, 2×300 mL portions ofsat. aq. NaCl, and dried (MgSO₄). After the solution was concentrated,the residue was purified by column chromatography (eluted with 7%EtOAc-Heptane) to afford the desired product in 7.8 g (78%) as a whitesolid. ¹H NMR (CDCl₃) 8.10 (d, 2H, J=9.0 Hz), 7.62 (d, 2H, J=9.0 Hz),7.59 (d, 2H, J=9.3 Hz), 7.48 (d, 2H, J=9.3 Hz), 3.95 (s, 3H)

Example 97

[0459] (4′-Bromo-biphenyl-4-yl)-methanol.

[0460] A solution of 4′-Bromo-biphenyl-4-carboxylic acid methyl ester,7.8 g (27.9 mmol) in 150 mL of tetrahydrofuran was cooled to 0° C. viaice-water bath. Lithium aluminum hydride, 1.1 g (27.9 mmol) was added tothe solution in one portion. The reaction mixture stirred at 0° C. for 1h. The mixture was slowly quenched with 10 mL of isopropyl alcohol, thenwith 10 mL of water. The aqueous mixture was extracted with 3×50 mLportions of ethyl acetate. The organic layers were combined, washed withsat. aq. NaCl, and dried (MgSO₄). The solution was concentrated toafford the desired product in 7.01 g (100%) as a white solid. Thematerial was taken to the next step without further purification.

Example 98

[0461] 4′-Bromo-4-bromomethyl-biphenyl.

[0462] A solution of (4′-bromo-biphenyl-4-yl)-methanol, 7.01 g (27.9mmol) and dibromo-triphenylphosphorane 11.8 g (27.9 mmol) in 150 mL ofmethylene chloride stirred at room temperature for 2 h. The solution wasdiluted with 100 mL of water and extracted with 2×200 mL portions ofdiethyl ether. The organic layers were combined, washed with sat. aq.NaCl, and dried (MgSO₄). After the solution was concentrated, theresidue was purified through a short plug of silica gel (eluted with 50%EtOAc-Heptane) to afford the desired product in 9.1 g (100%) as a whitesolid. The material was taken to the next step without furtherpurification.

Example 99

[0463]3-(4′-Bromobiphenyl-4-ylmethylsulfanyl)-2-tert-butoxycarbonylamino-propionicAcid Methyl Ester.

[0464] A mixture of 4′-Bromo-4-bromomethyl-biphenyl, 9.1 g (27.9 mmol),N-(tert-Butoxy-carbonyl)-L-cysteine methyl ester, 5.74 mL (27.9 mmol),cesium carbonate, 18.2 g (55.8 mmol), and 100 mL ofN,N-dimethylformamide was stirred at room temperature for 4 h. Themixture was diluted with 200 mL of water and extracted with 2×200 mL ofethyl acetate. The organic layer was washed with 2×200 mL portions ofaq. LiCl, sat. aq. NaHCO₃, sat. aq. NaCl, and dried (MgSO₄). After thesolution was concentrated, the residue was purified through a short plugof silica gel (eluted with 20% EtOAc-Heptane) to afford the desiredproduct in 8.8 g (66%) as a white solid. ¹H NMR (CDCl₃) 7.55 (d, 2H,J=9.3 Hz), 7.50 (d, 2H, J=9.0 Hz), 7.43 (d, 2H, J=9.3 Hz), 7.37 (d, 2H,J=9.0 Hz), 5.31 (d, 1H, J=9.0 Hz), 4.62-4.51 (m, 1H), 3.76 (s, 5H), 2.93(dd, 1H, 15.7, 5.7 Hz), 2.84 (dd, 1H, 15.7, 6.3 Hz), 1.47 (s, 9H).

Example 100

[0465]3-(4′-Benzo[1,3]dioxol-5-yl-biphenyl-4-ylmethylsulfanyl)-2-tert-butoxycarbonylamino-propionic Acid Methyl Ester.

[0466] A mixture of3-(4′-bromobiphenyl-4-ylmethylsulfanyl)-2-tert-butoxycarbonylamino-propionicacid methyl ester, 0.26 g (0.54 mmol), 3,4-methylenedioxyphenylboronicacid, 90 mg (0.54 mmol), Pd(PPh₃)₄, 63 mg (0.054 mmol), in 5 mL oftoluene and 3 mL of ethanol was heated to obtain a clear solution. Tothe solution was added 5 mL of 0.4M aq. Na₂CO₃. The reaction mixturerefluxed for 4 h at 80° C. The mixture was cooled to room temperatureand diluted with 100 mL ethyl acetate. The organic layer was washed with2×50 mL portions of water, 2×50 mL portions of sat. aq. NaCl, and dried(MgSO₄). After the solution was concentrated, the residue was purifiedby column chromatography (eluted with 7% EtOAc-Heptane) to afford thedesired product in 0.13 g (46%) as a white solid. ¹H NMR (CDCl₃)7.64-7.56 (m, 6H), 7.38 (d, 2H, J=9.3 Hz), 7.10 (dd, 2H, J=6.7, 2.0 Hz),6.90 (d, 1H, J=9.3 Hz), 6.01 (s, 2H), 5.32 (d, 1H, J=8.0 Hz), 4.63-4.52(m, 1H), 3.78 (s, 2H), 3.76 (s, 3H), 2.95 (dd, 1H, J=15.7, 5.3 Hz), 2.85(dd, 1H, J=15.7, 6.3 Hz), 1.47 (s, 9H).

Example 101

[0467]3-(4′-Benzo[1,3]dioxol-5-yl-biphenyl-4-ylmethylsulfanyl)-2-tert-butoxycarbonylamino-propionicAcid.

[0468] To a solution of3-(4′-benzo[1,3]dioxol-5-yl-biphenyl-4-ylmethylsulfanyl)-2-tert-butoxycarbonylamino-propionic acid, 130 mg (0.25 mmol) in 10 mL of tetrahydrofuran wasadded 1.25 mL of 6.0 M aq. KOH. The solution was stirred for 1 h at roomtemperature. The solution was diluted with 10 mL of water and acidifiedto pH 1-2. The aqueous was extracted with 3×30 mL portions of diethylether. The organic layers were combined, washed with sat. aq. NaHCO₃,sat. aq. NaCl, dried (MgSO₄). The solution was concentrated to affordthe desired product in 78 mg (61%) as an off-white solid. MP 178-180°C., Rf 0.25 (10% Methanol-90% Methylene Chloride); ¹H NMR (DMSO-d6) δ7.71-7.62 (m, 6H), 7.39 (d, 2H, J=9.3 Hz), 7.29 (d, 1H, J=2.0 Hz),7.20-7.13 (m, 2H), 6.99 (d, 1H, J=9.3 Hz), 6.05 (s, 2H), 4.19-4.08 (m,1H), 3.79 (s, 2H), 2.80 (dd, 1H, J=15.0, 5.7 Hz), 2.66 (dd, 1H, J=15.0,10.3 Hz), 1.40 (s, 9H). LCMS m/z calcd for C₂₈H₂₉NO₆S: 507.2 found508.0(M+1)

Example 102

[0469]3-(2″-Acetyl-[1,1′,4′1″]terphenyl-4-ylmethylsulfanyl)-2-tert-butoxycarbonylamino-propionicAcid Methyl Ester.

[0470] A mixture of3-(4′-bromobiphenyl-4-ylmethylsulfanyl)-2-tert-butoxycarbonylamino-propionicacid methyl ester, 0.26 g (0.54 mmol), 2-acetylphenylboronic acid, 89 mg(0.54 mmol), Pd(PPh₃)₄, 63 mg (0.054 mmol), in 5 mL of toluene and 3 mLof ethanol was heated to obtain a clear solution. To the solution wasadded 5 mL of 0.4M aq. Na₂CO₃. The reaction mixture refluxed for 4 h at80° C. The mixture was cooled to room temperature and diluted with 100mL ethyl acetate. The organic layer was washed with 2×50 mL portions ofwater, 2×50 mL portions of sat. aq. NaCl, and dried (MgSO₄). After thesolution was concentrated, the residue was purified by columnchromatography (eluted with 7% EtOAc-Heptane) to afford the desiredproduct in 0.11 g (39%) as a yellow oil. ¹H NMR (CDCl₃) δ 7.65 (d, 2H,J=9.3 Hz), 7.58 (t, 3H, J=9.3 Hz), 7.52 (d, 1H, J=7.7 Hz), 7.45-7.38 (m,6H), 5.32 (d, 1H, J=8.3 Hz), 4.63-4.52 (m, 1H), 3.78 (s, 2H), 3.77 (s,3H), 2.94 (dd, 1H, J=15.2, 5.3 Hz), 2.85 (dd, 1H, J=15.2, 6.3 Hz), 2.09(s, 3H), 1.47 (s, 9H).

Example 103

[0471]3-(2″-Acetyl-[1,1′,4′1″]terphenyl-4-ylmethylsulfanyl)-2-tert-butoxycarbonylamino-propionicAcid.

[0472] To a solution of3-(2″-acetyl-[1,1′,4′1″]terphenyl-4-ylmethylsulfanyl)-2-tert-butoxycarbonylamino-propionicacid methyl ester, 110 mg (0.21 mmol) in 10 mL of tetrahydrofuran wasadded 1.06 mL of 6.0M aq. KOH. The solution was stirred for 1 h at roomtemperature. The solution was diluted with 10 mL of water and acidifiedto pH 1-2. The aqueous was extracted with 3×30 mL portions of diethylether. The organic layers were combined, washed with sat. aq. NaHCO₃,sat. aq. NaCl, dried (MgSO₄). The solution was concentrated to affordthe desired product in 60 mg (56%) as a pale yellow foam. R_(f) 0.25(10% Methanol-90% Methylene Chloride); ¹H NMR (DMSO-d6) 7.73 (dd, 2H,J=9.0 Hz), 7.67 (d, 2H, J=9.0 Hz), 7.59 (dd, 2H, J=10.0, 8.3 Hz), 7.47(dd, 2H, J=10.0, 8.3 Hz), 7.40 (d, 2H, J=9.0 Hz), 7.37 (d, 2H, J=9.0Hz), 4.18-4.08 (m, 1H), 3.80 (s, 2H), 2.81 (dd, 1H, J=15.2, 5.3 Hz),2.66 (dd, 1H, J=15.2, 10.0 Hz), 2.20 (s, 3H), 1.40 (s, 9H). LCMS m/zcalcd for C₂₉H₃₁NO₅S: 505.2 found 506.1(M+1)

Example 104

[0473] 2-tert-Butoxycarbonylamino-3-(2″-methoxy-[1,1,′,4′,1″]terphenyl-4-ylmethylsulfanyl)-propionic acid methyl ester.

[0474] A mixture of3-(4′-bromobiphenyl-4-ylmethylsulfanyl)-2-tert-butoxycarbonylamino-propionicacid methyl ester, 0.26 g (0.54 mmol), 2-methoxyphenylboronic acid, 83mg (0.54 mmol), Pd(PPh₃)₄, 63 mg (0.054 mmol), in 5 mL of toluene and 3mL of ethanol was heated to obtain a clear solution. To the solution wasadded 5 mL of 0.4M aq. Na₂CO₃. The reaction mixture refluxed for 4 h at80° C. The mixture was cooled to room temperature and diluted with 100mL ethyl acetate. The organic layer was washed with 2×50 mL portions ofwater, 2×50 mL portions of sat. aq. NaCl, and dried (MgSO₄). After thesolution was concentrated, the residue was purified by columnchromatography (eluted with 7% EtOAc-Heptane) to afford the desiredproduct in 80 mg (29%) as a white solid. ¹H NMR (CDCl₃) 7.61-7.57 (m,6H), 7.39-7.30 (m, 4H), 7.06 (d, 1H, J=8.0 Hz), 7.00 (d, 1H, J=9.7 Hz),5.35 (d, 1H, J=8.7 Hz), 4.63-4.52 (m, 1H), 3.85 (s, 3H), 3.78 (s, 2H),3.76 (s, 3H), 2.95 (dd, 1H, J=15.3, 5.3 Hz), 2.85 (dd, 1H, J=15.3, 6.7),1.48 (s, 9H).

Example 105

[0475]2-tert-Butoxycarbonylamino-3-(2″-methoxy-[1,1′,4′,1′]terphenyl-4-ylmethylsulfanyl)-propionicacid.

[0476] To a solution of2-tert-butoxycarbonylamino-3-(2″-methoxy-[1,1′,4′,1″]terphenyl-4-ylmethylsulfanyl)-propionicacid methyl ester, 80 mg (0.16 mmol) in 10 mL of tetrahydrofuran wasadded 0.79 mL of 6.0M aq. KOH. The solution was stirred for 1 h at roomtemperature. The solution was diluted with 10 mL of water and acidifiedto pH 1-2. The aqueous was extracted with 3×30 mL portions of diethylether. The organic layers were combined, washed with sat. aq. NaHCO₃,sat. aq. NaCl, dried (MgSO₄). The solution was concentrated to affordthe desired compound in 17 mg (22%) as a pale yellow foam. Rf 0.25 (10%Methanol-90% Methylene Chloride); ¹H NMR (DMSO-d6) 7.69-7.63 (m, 3H),7.54 (d, 2H, J=9.0 Hz), 7.39 (d, 2H, J=9.0 Hz), 7.32 (d, 2H, 8.0 Hz),7.17-7.10 (m, 2H), 7.03 (t, 1H, J=8.0 Hz), 4.19-4.08 (m, 1H), 3.80 (s,2H), 3.78 (s, 3H), 2.81 (dd, 1H, J=15.3, 5.0 Hz), 2.67 (dd, 1H, J=15.3,10.0 Hz), 1.40 (s, 9H). LCMS m/z calcd for C₂₈H₃₁NO₅S: 493.2 found494.4(M+1).

Example 106

[0477]2-tert-Butoxycarbonylamino-3-(4′-dibenzothiophen-4-yl-biphenyl-4-ylmethyl-sufanyl)-propionicAcid Methyl Ester.

[0478] A mixture of3-(4′-bromobiphenyl-4-ylmethylsulfanyl)-2-tert-butoxycarbonylamino-propionicacid methyl ester, 0.33 g (0.69 mmol), 4-dibenzothiopheneboronic acid,0.19 g (0.82 mmol), Pd(PPh₃)₄, 80 mg (0.069 mmol), in 5 mL of tolueneand 3 mL of ethanol was heated to obtain a clear solution. To thesolution was added 5 mL of 0.4M aq. Na₂CO₃. The reaction mixturerefluxed for 4 h at 80° C. The mixture was cooled to room temperatureand diluted with 100 mL ethyl acetate. The organic layer was washed with2×50 mL portions of water, 2×50 mL portions of sat. aq. NaCl, and dried(MgSO₄). After the solution was concentrated, the residue was purifiedby column chromatography (eluted with 7% EtOAc-Heptane) to afford thedesired product in 300 mg (75%) as a white solid. ¹H NMR (CDCl₃)8.26-8.16 (m, 2H), 7.86-7.82 (m, 3H), 7.74 (d, 2H, J=9.3 Hz), 7.64 (d,2H, J=9.3 Hz), 7.60-7.44 (m, 6H), 5.35 (d, 1H, J=12.5 Hz), 4.63-4.52 (m,1H), 3.80 (s, 2H), 3.78 (s, 3H), 2.97 (dd, 1H, J=15.3, 5.3 Hz), 2.89(dd, 1H, J=15.3, 6.3), 1.49 (s, 9H)

Example 107

[0479]2-tert-Butoxycarbonylamino-3-(4′-dibenzothiophen-4-yl-biphenyl-4-ylmethyl-sufanyl)-propionicAcid.

[0480] To a solution of2-tert-Butoxycarbonylamino-3-(4′-dibenzothiophen-4-yl-biphenyl-4-ylmethyl-sufanyl)-propionicacid methyl ester, 0.27 g (0.51 mmol) in 10 mL of tetrahydrofuran wasadded 0.43 mL of 6.0M aq. KOH. The solution was stirred for 1 h at roomtemperature. The solution was diluted with 10 mL of water and acidifiedto pH 1-2. The aqueous was extracted with 3×30 mL portions of diethylether. The organic layers were combined, washed with sat. aq. NaHCO₃,sat. aq. NaCl, dried (MgSO₄), and filtered. The solution wasconcentrated to afford the desired compound in 0.21 g (72%) as a paleyellow solid. MP 108-110° C., Rf 0.25 (10% Methanol-90% MethyleneChloride); ¹H NMR (DMSO-d6) 8.20-8.15 (m, 2H), 7.87-7.80 (m, 3H), 7.72(d, 2H, J=9.3 Hz), 7.63 (d, 2H, J=9.3 Hz), 7.57-7.35 (m, 6H), 5.40 (d,1H, J=7.0 Hz), 4.63-4.52 (m, 1H), 3.830 (s, 2H), 2.99 (dd, 1H, J=15.3,5.3 Hz), 2.91 (dd, 1H, J=15.3, 6.3), 1.48 (s, 9H). LCMS m/z calcd forC₃₃H₃₁NO₄S₂: 569.2 found 570.4(M+1)

Example 108

[0481](2R)-Methyl-3-(4-amino-benzylsulfanyl)-2-tert-butoxycarbonylamino-propionate.

[0482] A mixture of 1-bromomethyl-4-nitro-benzene (2.15 g, 9.95 mmol),cesium carbonate (6.49 g, 19.9 mmol) and2-tert-butoxycarbonylamino-3-mercapto-propionic acid methyl ester (2.46g, 10.5 mmol) in DMF (25 mL) was stirred at room temperature. Uponcompletion of the reaction (TLC control: 30% ethyl acetate in heptane),the reaction mixture was quenched with water (50 mL) and extracted withdiethyl ether (3×50 mL). The combined extract was washed sequentiallywith water and brine, dried over anhydrous MgSO₄, filtered andconcentrated in vacuo. Purification by flash chromatography (SiO₂; 30%ethyl acetate in heptane as eluent) yielded the thioether as anoff-white solid.

[0483] A mixture of(2R)-methyl-2-tert-butoxycarbonylamino-3-(4-nitro-benzylsulfanyl)-propionate(3.75 g, 10.1 mmol) and tin (II) chloride (5.76 g, 30.0 mmol) inmethanol (50 mL) was stirred at 50° C. Upon completion (TLC: 5% methanolin dichloromethane), the mixture was cooled to room temperature,quenched with saturated potassium fluoride solution (75 mL) andextracted with diethyl ether (3×75 mL). The combined extract was washedsequentially with water and brine, dried over anhydrous MgSO₄, filteredand concentrated in vacuo. Flash chromatography purification (SiO₂; 1-2%methanol in dichloromethane as eluent) yielded the titled compound as anoff-white solid. ¹H NMR (CDCl₃, 300 MHz) δ 7.08 (2H, d, J=8 Hz, ArH),6.25 (2H, d, J=8 Hz, ArH), 4.53 (1H, m, CHN), 3.75 (3H, s, OCH₃), 3.63(2H, s, PhCH₂S), 2.84 (2H, m, CH ₂CHN), 1.46 (9H, s, CMe₃); ESI-LCMS e/zcalculated for C₁₆H₂₄N₂O₄S 340.146, found 341 (M+H)⁺, 363 (M+Na)⁺.

Example 109

[0484] Indol-1-yl-acetic Acid.

[0485] 1H-indole (5.0 g, 42.7 mmol) in anhydrous DMF (10 mL) was addedto a suspension of sodium hydride (1.13 g, 46.9 mmol) in anhydrous DMF(20 mL) in a flame dried flask at 0° C. stirred under nitrogenatmosphere. Fifteen minutes after gas evolution had ceased, bromo-aceticacid ethyl ester (5.7 mL, 51.2 mmol) was added and the reaction washeated to 70° C. and stirred under nitrogen. Upon completion (TLC: 50%dichloromethane in heptane), the reaction mixture was quenched withwater (50 mL) and extracted with diethyl ether (3×50 mL). The combinedextract was washed sequentially with water and brine, dried overanhydrous MgSO₄, filtered and concentrated in vacuo. To a solution ofcrude indol-1-yl-acetic acid ethyl ester (9.37 g, 46.2 mmol) in methanol(20 mL) and THF (80 mL) was added 6N NaOH solution (25 mL). Uponcompletion (TLC: 10% methanol in dichloromethane), the mixture wasacidified with 6N HCl solution to pH 2, and extracted with ethyl acetate(3×75 mL). The combined extract was washed sequentially with water andbrine, dried over anhydrous MgSO₄, filtered and concentrated in vacuo toyield the crude titled compound as a light brown solid. ¹H NMR (DMSO-d6,300 MHz) δ 7.51 (1H, dd, J=8, 1 Hz, Ar—H), 7.35 (1H, dd, J=8, 1 Hz,Ar—H), 7.30 (1H, d, J=3 Hz, Ar—H), 7.09 (1H, td, J=7.5, 1 Hz, Ar—H),6.99 (1H, td, J=7.5, 1 Hz, Ar—H), 6.41 (1H, dd, J=3, 1 Hz, Ar—H), 4.99(2H, s, CH₂).

Example 110

[0486] (5-Fluoro-indol-1-yl)-acetic Acid.

[0487] (5-Fluoro-indol-1-yl)-acetic acid was prepared in analogousfashion to that exemplified in Example 109, except 5-fluoro-1H-indolewas substituted for 1H-indole. ¹H NMR (CDCl₃, 300 MHz) δ 7.27 (1H, dd,J=9, 2 Hz, Ar—H), 7.14 (1H, dd, J=9, 4 Hz, Ar—H), 7.10 (1H, d, J=3 Hz,Ar—H), 6.97 (1H, td, J=9, 2.5 Hz, Ar—H), 6.53 (1H, d, J=3 Hz, Ar—H),4.88 (2H, s, CH₂)

Example 111

[0488] (5-Benzyloxy-indol-1-yl)-acetic Acid.

[0489] (5-Benzyloxy-indol-1-yl)-acetic acid was prepared in analogousfashion to that exemplified in Example 109, except 5-benzyloxy-1H-indolewas substituted for 1H-indole. ¹H NMR (DMSO-d6, 300 MHz) δ 7.45-7.24(7H, m, Ar—H), 7.10 (1H, d, J=2 Hz, Ar—H), 6.82 (1H, dd, J=9, 2 Hz,Ar—H), 6.31 (1H, d, J=3 Hz, Ar—H), 5.07 (2H, d, J=4 Hz, PhCH₂O), 4.94(2H, s, CH₂N).

Example 112

[0490](2R)-2-tert-Butoxycarbonylamino-3-[4-(2-indol-1-yl-acetylamino)-benzylsulfanyl]-propionicAcid.

[0491] A solution of indol-1-yl-acetic acid (1.25 g, 7.14 mmol),(2R)-3-(4-amino-benzylsulfanyl)-2-tert-butoxycarbonylamino-propionicacid methyl ester (2.67 g, 7.85 mmol), EDC (1.71 g, 8.93 mmol),triethylamine (2.48 mL, 17.85 mmol) and DMAP (87 mg, 0.714 mmol) in DCM(50 mL) was stirred at ambient temperature. Upon completion (TLC: 2%methanol in dichloromethane), the reaction was quenched with water (75mL) and extracted with ethyl acetate (3×50 mL). The combined extract waswashed sequentially with water and brine, dried over anhydrous MgSO₄,filtered, concentrated in vacuo and purified by flash chromatography(SiO₂; 30-40% ethyl acetate/heptane as eluent). To a stirred solution of(2R)-2-tert-butoxycarbonylamino-3-[4-(2-indol-1-yl-acetylamino)-benzylsulfanyl]-propionicacid methyl ester (0.470 g, 0.945 mmol) in methanol (3 mL) and THF (12mL) was added 2N NaOH solution (2.5 mL, 5.3 mmol). Upon completion (TLC10% methanol in dichloromethane), the mixture was acidified to pH 2 with2N HCl solution and extracted with ethyl acetate (3×20 mL). The combinedextract was washed sequentially with water and brine, dried overanhydrous MgSO₄, filtered and concentrated in vacuo to yield the titledcompound as a light yellow solid. R_(f) 0.40 (20% methanol indichloromethane); ¹H NMR (CDCl₃, 300 MHz) δ 7.71 (1H, d, J=7 Hz, Ar—H),7.37-7.20 (6H, m, Ar—H), 7.16 (1H, d, J=3 Hz, Ar—H), 7.00 (1H, m, Ar—H),6.69 (1H, d, J=3 Hz, Ar—H), 4.95 (2H, s, NCH₂CO), 4.38 (1H, m, CHN),3.66 (2H, s, PhCH₂S), 2.85 (2H, m, CH ₂CHN), 1.45 (9H, s, CMe₃);ESI-LCMS e/z calculated for C₂₅H₂₉N₃O₅S 483.183, found 484 (M+H)⁺, 506(M+Na)⁺.

Example 113

[0492](2R)-2-tert-Butoxycarbonylamino-3-{4-[2-(5-fluoro-indol-1-yl)-acetylamino]-benzylsulfanyl}-propionicAcid.

[0493](2R)-2-tert-Butoxycarbonylamino-3-{4-[2-(5-fluoro-indol-1-yl)-acetylamino]-benzylsulfanyl}-propionicacid was prepared in analogous fashion to that exemplified in Example112, except (5-fluoro-indol-1-yl)-acetic acid was substituted forindol-1-yl-acetic acid. R_(f) 0.35 (20% methanol in dichloromethane); ¹HNMR (CDCl₃, 300 MHz) δ 7.32 (1H, dd, J=9, 2.5 Hz, Ar—H), 7.23-7.11 (6H,m, Ar—H), 7.00 (1H, td, J=9, 2.5 Hz, Ar—H), 6.61 (1H, d, J=3 Hz, Ar—H),4.90 (2H, s, NCH₂CO), 4.44 (1H, m, CHN), 3.64 (2H, s, PhCH₂S), 2.82 (2H,m, CH₂CHN), 1.44 (9H, s, CMe₃); ESI-LCMS e/z calculated for C₂₅H₂₈FN₃O₅S501.173, found 502 (M+H)⁺, 524 (M+Na)⁺.

Example 114

[0494](2R)-3-{4-[2-(5-Benzyloxy-indol-1-yl)-acetylamino]-benzylsulfanyl}-2-tert-butoxycarbonylamino-propionicAcid.

[0495](2R)-3-{4-[2-(5-Benzyloxy-indol-1-yl)-acetylamino]-benzylsulfanyl}-2-tert-butoxycarbonylamino-propionicacid was prepared in analogous fashion to that exemplified in Example112, except (5-benzyloxy-indol-1-yl)-acetic acid was substituted forindol-1-yl-acetic acid. R_(f) 0.58 (20% methanol in dichloromethane); ¹HNMR (DMSO-d6, 300 MHz) δ 10.33 (1H, s, COOH), 7.52-7.20 (10H, m, Ar—H),7.12 (1H, d, J=2 Hz, Ar—H), 6.83 (1H, dd, J=9, 2 Hz, Ar—H), 6.33 (1H, d,J=3 Hz, Ar—H), 5.08 (2H, s), 4.97 (2H, s), 4.03 (1H, m, CHN), 3.68 (2H,s, PhCH₂S), 2.67 (2H, m, CH ₂CHN), 1.38 (9H, s, CMe₃); ESI-LCMS e/zcalculated for C₃₂H₃₅N₃O₆S 589.225, found 590 (M+H)⁺, 612 (M+Na)⁺.

Example 115

[0496](2R)-2-tert-Butoxycarbonylamino-3-{4-[2-(5-fluoro-indol-1-yl)-acetylamino]-phenylmethanesulfinyl}-propionicAcid.

[0497] To a stirred solution of(2R)-2-tert-butoxycarbonylamino-3-{4-[2-(5-fluoro-indol-1-yl)-acetylamino]-benzylsulfanyl}-propionicacid (460 mg, 0.917 mmol) in acetic acid (20 mL) was added sodiumperborate tetrahydrate (148 mg, 0.963 mmol). This solution was stirredat 40° C. until complete (TLC: 20% methanol in dichloromethane), thencooled to room temperature, diluted with ethyl acetate (100 mL), washedsequentially with water and brine, dried over anhydrous MgSO₄, filteredand concentrated in vacuo. Purification by flash chromatography (SiO₂;10-20% methanol in dichloromethane as eluent) yielded the titledcompound as a 1:1 mixture of diastereomers as an off-white solid. R_(f)0.09 (20% methanol in dichloromethane); ¹H NMR (DMSO-d6, 300 MHz) δ 7.32(2H, d, J=9 Hz, Ar—H), 7.44-7.34 (2H, m, Ar—H), 7.31-7.19 (3H, m, Ar—H),6.94 (1H, td, J=9, 2.5 Hz, 6.43 (1H, d, J=3 Hz, Ar—H), 5.07 (2H, s,NCH₂CO), 4.23-3.80 (3H, m, PhCH₂S and CHN), 2.87 (2H, m, CH ₂CHN), 1.37and 1.35 (both 4.5H, s, CMe₃ diastereomers); ESI-LCMS e/z calculated forC₂₅H₂₈FN₃O₆S 517.168, found 518 (M+H)⁺, 540 (M+Na)⁺.

Example 116

[0498]N-[4′-(2-Butyl-benzofuran-3-ylmethyl)-4-(3-phenyl-propoxy)-biphenyl-3-yl]-oxalamicAcid

[0499] Step 1: (4-Bromo-phenyl)-(2-butyl-benzofuran-3-yl)-methanone

[0500] A solution of 2-n-butylbenzofurane (19.8 g, 114 mmol) and4-bromobenzoyl chloride (25.0 g, 114 mmol) in dry dichloromethane (300mL, 0.4 M) was cooled to 0° C. and treated with AlCl₃ (16.6 g, 1.1equiv., 125.4 mmol) in 3 portions. After the additions were complete,the solution was stirred for 3 h and carefully added to ice water. Afterseparation, the aqueous layer was extracted with dichloromethane (2×200mL) and the combined organic layers were washed with water, sat'd aqNaCl, dried over anhydrous MgSO₄, filtered and concentrated in vacuo.Purification by flash column chromatography (1-2% ethyl acetate inheptane) afforded (4-bromo-phenyl)-(2-butyl-benzofuran-3-yl)-methanone(14.6 g, 36%).

[0501] Step 2: 3-(4-Bromo-benzyl)-2-butyl-benzofuran

[0502] A solution of(4-bromo-phenyl)-(2-butyl-benzofuran-3-yl)-methanone (2.25 g, 6.32 mmol)in ethanol (20 mL, 0.3 M) was cooled to 0° C. and treated with NaBH₄(0.263 g, 1.1 equiv, 6.95 mmol). After stirring for 1 h, the mixture waspoured into a 50% ether in water solution (200 mL). After separation,the aqueous layer was extracted with ether (50 mL) and the combinedorganic layers were washed with water, sat'd aq NaCl, dried overanhydrous MgSO₄, filtered and concentrated in vacuo. The resultingalcohol was subsequently disolved in dry dichloromethane (50 mL), cooledto 0° C. and treated with triethylsilane (2.0 mL, 2.0 equiv., 12.64mmol) dropwise via syringe. After stirring an additional 5 min,trifluoroacetic acid (2.43 mL, 5.0 equiv., 31.6 mmol) was added over 2min and the mixture was stirred for 3 h. Once complete, the solution waswashed with water, sat'd aq NaCl, dried over anhydrous MgSO₄, filteredand concentrated in vacuo. Purification by flash column chromatography(0-2% ethyl acetate in heptane) afforded3-(4-bromo-benzyl)-2-butyl-benzofuran as a pale yellow oil (1.34 g,63%).

[0503] Step 3:2-Butyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-benzofuran

[0504] A solution of 3-(4-bromo-benzyl)-2-butyl-benzofuran (14.03 g,41.5 mmol), bis(pinacolato)diborane (11.60 g, 1.1 equiv., 45.7 mmol),potassium acetate (12.2 g, 3.0 equiv., 125 mmol) in DMSO (100 mL, 0.4 M)was treated with PdCl₂(dppf).CH₂Cl₂ (4.15 g, 0.1 equiv., 4.15 mmol) andheated to 80° C. After compete by TLC, the solution was coled to roomtemperature, diluted with water (150 mL) and filtered through celite(washed with ether, 500 mL). After separation, the aqueous layer wasextracted with ether (2×150 mL). The combined organic layers were washedwith water, sat'd aq NaCl, dried over anhydrous MgSO₄, filtered andconcentrated in vacuo. Purification by flash column chromatography (2-5%ethyl acetate in heptane) afforded2-butyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-benzofuranas a pale yellow oil (11.2 g, 69%).

[0505] Step 4:2-Butyl-3-[3′-nitro-4′-(3-phenyl-propoxy)-biphenyl-4-ylmethyl]-benzofuran

[0506] A solution of2-butyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-benzofuran(100 mg, 0.256 mmol), 4-bromo-2-nitro-1-(3-phenylpropylox)-benzene (95mg, 1.1 equiv., 0.282 mmol) and K₂CO₃ (136 mg, 3.5 equiv., 0.987 mmol)in water (1 mL) and DMF (2 mL) was treated with PdCl₂(dppf).CH₂Cl₂ (23mg, 0.1 equiv., 0.0282 mmol) and heated to 120° C. After complete (byTLC) the solution was cooled to room temperature, acidified to pH<4 with10% aq HCl and diluted with water (20 mL). After separation, the aqueouslayer was extracted with ether (3×20 mL) and the combined organic layerswere washed with water, sat'd aq NaCl, dried over anhydrous MgSO₄,filtered and concentrated in vacuo. Purification by prep thin layerchromatography afforded2-butyl-3-[3′-nitro-4′-(3-phenyl-propoxy)-biphenyl-4-ylmethyl]-benzofuran(53 mg, 41%).

[0507] Step 5:4′-(2-Butyl-benzofuran-3-ylmethyl)-4-(3-phenyl-propoxy)-biphenyl-3-ylamine

[0508] A solution of2-butyl-3-[3′-nitro-4′-(3-phenyl-propoxy)-biphenyl-4-ylmethyl]-benzofuran(53 mg, 0.105 mmol) in ethanol (1 mL) and acetic acid (1 mL) was treatedwith Fe (26.4 mg, 4.5 equiv., 0.472 mmol) and heated to 120° C. for 3 h.After cooling to room temperature, the solution was poured into a 20% aqNaOH/ice water solution (Ph>8) and extracted with ether (3×20 mL). Thecombined organic layers were washed with water, sat'd aq NaCl, driedover anhydrous MgSO₄, filtered and concentrated in vacuo. Purificationby prep thin layer chromatography (25% ethyl acetate in heptane)afforded4′-(2-butyl-benzofuran-3-ylmethyl)-4-(3-phenyl-propoxy)-biphenyl-3-ylamine(14.5 mg, 29%).

[0509] Step 6:N-[4′-(2-Butyl-benzofuran-3-ylmethyl)-4-(3-phenyl-propoxy)-biphenyl-3-yl]-oxalamicAcid Ethyl Ester

[0510] A solution of4′-(2-butyl-benzofuran-3-ylmethyl)-4-(3-phenyl-propoxy)-biphenyl-3-ylamine(129 mg, 0.264 mmol) and diisopropylethylamine (0.115 mL, 2.5 equiv.,0.66 mmol) in dichloromethane (5 mL) was treated with a solution ofethyl chlorooxoacetate (44 mg, 1.2 equiv., 0.317 mmol) indichloromethane (1 mL). After stirring for 2 h, the solution was dilutedwith water and extracted with dichloromethane (2×15 mL). The combinedorganic layers were washed with water, sat'd aq NaCl, dried overanhydrous MgSO₄, filtered and concentrated in vacuo. Purification byprep thin layer chromatography (25% ethyl acetate in heptane) affordedN-[4′-(2-butyl-benzofuran-3-ylmethyl)-4-(3-phenyl-propoxy)-biphenyl-3-yl]-oxalamicacid ethyl ester (120 mg, 77%).

[0511] Step 7:N-[4′-(2-Butyl-benzofuran-3-ylmethyl)-4-(3-phenyl-propoxy)-biphenyl-3-yl]-oxalamicAcid

[0512] A solution ofN-[4′-(2-butyl-benzofuran-3-ylmethyl)-4-(3-phenyl-propoxy)-biphenyl-3-yl]-oxalamicacid ethyl ester (120 mg, 0.204 mmol) in ethanol (3 mL) was treated withaq 1 N NaOH (0.3 mL, 1.5 equiv., 0.306 mmol) and stirred at roomtemperature. After stirring 1 h, the solution was acidified to pH<4 with10% HCl, concentrated and purified by prep thin layer chromatography(10% methanol in dichloromethane) affordedN-[4′-(2-Butyl-benzofuran-3-ylmethyl)-4-(3-phenyl-propoxy)-biphenyl-3-yl]-oxalamicacid (32 mg, 28%).

Example 117

[0513] 4-Dibenzofuran-4-yl-phenyl-boronic Acid

[0514] Step 1: (4-Dibenzofuran-4-yl-phenyl)-trimethyl-silane

[0515] A solution of dibenzofuran-4-yl-boronic acid (20.0 g, 94.3 mmol),(4-bromo-phenyl)-trimethyl-silane (21.62 g, 94.3 mmol), K₂CO₃ (39.1 g, 3equiv., 283 mmol) in toluene (100 mL), ethanol (60 mL) and water (30 mL)was purged with nitrogen for 5 min (bubbled into solution) and treatedwith Pd(PPh₃)₄ (3.59 g, 2.9 mmol). After heating to 80° C. for 4 h, thesolution was cooled to room temperature, poured into water (300 mL) andextracted with ethyl acetate (300 mL). The organic phase was washed withsat'd aq NaCl, dried over anhydrous MgSO₄, filtered and concentrated invacuo. Purification by flash column chromatography (5-20% ethyl acetatein heptane) afforded (4-dibenzofuran-4-yl-phenyl)-trimethyl-silane as acolorless oil (28.9 g, 96%).

[0516] Step 2: 4-Dibenzofuran-4-yl-phenyl-boronic Acid

[0517] A solution of (4-dibenzofuran-4-yl-phenyl)-trimethylsilane (28 6g, 90.2 mmol) in dichloromethane (350 mL, 0.26 M) was cooled to −78° C.and carefully treated with borontribromide (135 mL, 1.5 equiv., 135mmol). After the addition was complete, the solution was warmed to roomtemperature and stirred for 3 h. Next, the reaction mixture wasre-cooled to −78° C., treated with dry methanol (30 mL), slowly warmedto room temperature and stirred for 1.5 h. Next, the solution wasre-cooled to −78° C., carefully quenched with 10% aq HCl (50 mL), warmedto room temperature and stirred for 1 h (solids form). The resultingsolution was poured into water (500 mL) and extracted with ethyl acetate(3×700 mL). The combined organic layers were washed with sat'd aq NaCl,dried over anhydrous MgSO₄, filtered and concentrated in vacuo. Thecrude product was suspended in a 10% ethyl acetate in heptane solution,filtered and washed with the same solution (5×60 mL) to give4-dibenzofuran-4-yl-phenyl-boronic acid as a white solid (20.2 g, 77%).

Example 118

[0518] The following compounds were prepared essentially according tothe methods and schemes described above.

[0519]2-tert-Butoxycarbonylamino-3-[4-(6-dibenzofuran-4-yl-pyridin-3-yl)-benzylsulfanyl]-propionicAcid.

[0520] R_(f) 0.70 (50% methanol in ethyl acetate).

[0521]2-tert-Butoxycarbonylamino-3-[4-(2-dibenzofuran-4-yl-thiazol-5-yl)-benzylsulfanyl]-propionicAcid.

[0522] R_(f) 0.81 (50% methanol in ethyl acetate).

Example 119

[0523]2-tert-Butoxycarbonylamino-3-[4-(5-dibenzofuran-4-yl-6-methyl-pyridin-2-yl)-benzylsulfanyl]-propionicAcid.

[0524] R_(f) 0.64 (20% methanol in ethyl acetate).

Example 120

[0525]2-tert-Butoxycarbonylamino-4-(4′-dibenzofuran-4-yl-biphenyl-4-yloxy)butryicAcid

[0526] 1. (L)-N-tert-Butoxycarbonylhomoserine

[0527] A solution of homoserine (5.0 g, 42 mmol) and triethylamine (8.8mL, 63 mmol) in 50% aq acetone (25 mL) was cooled to 0° C. and treatedwith di-tert-butyl dicarbonate (10.1 g, 46.4 mmol). After stirring 16 h,the reaction mixture was concentrated to give crude(L)-N-tert-butoxycarbonylhomoserine triethylamine salt (13.4 g). Thecrude product was used without further purification.

[0528] 2. (L)-N-tert-Butoxycarbonylhomoserine Methyl Ester

[0529] A solution of crude (L)-N-tert-butoxycarbonylhomoserinetriethylamine salt (13.4 g, 42 mmol) in DMF (25 mL) was treated withmethyliodide (3.2 mL, 46 mmol). After stirring for 16 h, the reactionmixture was diluted with ethyl acetate (100 mL), washed successivelywith 5% citric acid, sat. aq NaHCO₃, sat. aq NaCl, dried over MgSO₄,filltered and concentrated. Purification by flash column chromatography(25% ethyl acetate in heptane) gave (L)-N-tert-butoxycarbonylhomoserinemethyl ester (7.8 g, 80% two steps). ¹H NMR (CDCl₃) 5.32 (d, J=12 Hz,1H), 4.56 (m, 1H), 4.09 (T, J=10 Hz, 2H), 3.79 (s, 3H), 2.38 (m, 2H),1.61 (s, 9H).

[0530] 3. (L)-2-tert-Butoxycarbonylamino-4-bromobutyric Acid MethylEster

[0531] A solution of (L)-N-tert-butoxycarbonylhomoserine methyl ester(1.2 g, 5.14 mmol) and carbontetrabromide (2.52 g, 7.71 mmol) indichloromethane (20 mL) was treated with a second solution oftriphenylphosphine (1.34 g, 5.14 mmol) in dichloromethane (15 mL). Afterstirring at room temperature for 16 h, the solution was diluted withheptane (50 mL). The resulting precipitate was filtered and successivelywashed with heptane, 5% NaHCO₃, sat. aq NaCl, dried over MgSO₄ andconcentrated. Purification by by flash column chromatography (10% ethylacetate in heptane) gave (L)-2-tert-butoxycarbonylamino-4-bromobutyricacid methyl ester as white solid (1.19 g, 78%). ¹H NMR (CDCl₃), δ 5.10(d, J=5 Hz, 1H), 4.38 (t, J=15 Hz, 1H), 3.77 (s, 3H), 3.44 (t, J=13 Hz,2H), 2.40 (m, 1H), 2.21 (m, 1H), 1.42 (s, 9H)

[0532] 4. 4-(4′-bromobiphen-4-yloxy)-2-tert-butoxycarbonylaminobutyricAcid Methyl Ester

[0533] A solution of 4′-bromobipheny-4-ol (883 mg, 3.55 mmol) in DMF (10mL) was treated with NaH (148 mg, 3.72 mmol). After stirring for 10 min,(L)-4-bromo-2-tert-butoxycarbonylamino-butyric acid methyl ester (1 g,3.38 mmol) was added and the reaction mixture was stirred an additional16 h. Once complete, the reaction mixture was diluted with ethyl acetate(100 mL), washed successively with sat. aq NH₄Cl and sat. aq NaCl, driedover MgSO₄, filtered, and concentrated. Purification by flash columnchromatography (10% ethyl acetate in heptane) provided4-(4′-bromobiphen-4-yloxy)-2-tert-butoxycarbonylaminobutyric acid methylester as white solid (0.79 g, 50%). ¹H NMR (CDCl₃), δ 7.50 (d, J=8 Hz,2H), 7.44 (d, J=8 Hz, 2H), 7.38 (d, J=8 Hz, 2H), 6.92 (d, J=8 Hz, 2H),5.28 (m, 1H), 4.51 (m, 1H), 4.08 (t, J=8 Hz, 2H), 3.77 (s, 3H), 2.34 (m,2H), 1.44 (s, 9H). LCMS, 466 (M⁺+1).

[0534] 5.2-tert-Butoxycarbonylamino-4-(4′-dibenzofuan-4-yl-biphenyl-4-yloxy)butryicAcid Methyl Ester

[0535] A solution of4-(4′-bromobiphen-4-yloxy)-2-tert-butoxycarbonylaminobutyric acid methylester (464 mg, 1 mmol), 4-dibenzofuranboronic acid (222 mg, 1.1 mmol)and Pd(PPh₃)₄ (52 mg, 5% mol) in toluene (10 mL) and ethanol (3 mL) washeated until the solution became clear and subsequently treated with 2 MK₂CO₃ (1.5 mL). The reaction mixture was heated to reflux for 2 h,cooled to room temperature, diluted with ethyl acetate (100 mL). Theorganic layer was washed successively with sat. aq NH₄Cl and sat. aqNaCl, dried over MgSO₄ and concentrated. Purification by flash columnchromatography (2-10% ethyl acetate in heptane) provided2-tert-Butoxycarbonylamino-4-(4′-dibenzofuan-4-yl-biphenyl-4-yloxy)butryicacid methyl ester as white solid (374 mg, 69%). ¹H NMR (CDCl₃), 7.95 (m,4H), 7.70 (d, J=8 Hz, 2H), 7.62 (m, 4H), 7.43 (m, 3H), 6.96 (d, J=8 Hz,2H), 5. 33 (d, J=8 Hz, 1H), 4.53 (m, 1H), 4.11 (t, J=8 Hz, 2H), 3.78 (s,3H), 2.34 (m, 2H), 1.45 (s, 9H). LCMS 552 (M⁺+1).

[0536] 6.2-tert-Butoxycarbonylamino-4-(4′-dibenzofuran-4-yl-biphenyl-4-yloxy)butryicAcid

[0537] A solution of2-tert-Butoxycarbonylamino-4-(4′-dibenzofuan-4-yl-biphenyl-4-yloxy)butryicacid methyl ester (280 mg, 0.51 mmol) in THF (2 mL) and methanol (2 mL)was cooled to 0° C. and treated with 2 N KOH (1.25 mL). After stirring 1h, the solution was quenched with 10% HCl (to pH 2) and diluted withethyl acetate (25 mL). After organic layer was seperated the aqueouslayer was extracted with ethyl acetate (3×15 mL) and the combinedorganic layers were dried over MgSO₄ and concentrated. Purification byflash column chromatography (2-5% methanol in dichloromethane) provided2-tert-Butoxycarbonylamino-4-(4′-dibenzofuan-4-yl-biphenyl-4-yloxy)butryicacid as white solid (250 mg, 91%). ° C., ¹H NMR (DMSO-d6), 8.15 (q, J=8Hz, 2H), 7.95 (d, J=8 Hz, 2H) 7.71 (m, 6H), 7.49 (m, 3H), 7.01 (d, J=8Hz, 2H), 6.83 (m, 1H), 4.04 (t, J=6 Hz, 2H), 2.15 (m, 1H), 2.00 (m, 1H),1.36 (s, 9H). LCMS 538 (M⁺+1).

Example 121

[0538]2-tert-Butoxycarbonylamino-4-(4′-dibenzofuan-4-yl-biphenyl-4-ylsulfanyl)-butryicAcid

[0539] 1. 4-(4′-bromophenylsulfanyl)-2-tert-ButoxycarbonylaminobutryicAcid Methyl Ester

[0540] A solution of 4-bromobenzenethiol (670 mg, 3.55 mmol) and(L)-4-bromo-2-tert-butoxycarbonylamino-butyric acid methyl ester (1 g,3.38 mmol) in DMF (15 mL) was cooled to 0° C. and treated with Cs₂CO₃(1.2 g, 3.7 mmol) Once the addition was complete, the reaction mixturewas warmed to room temperature, stirred for 2 h, diluted with ethylacetate (100 mL) and washed sucssevely with sat. aq NH₄Cl and sat. aqNaCl. The resulting solution was dried over MgSO₄ concentrated andpurified by flash column chromatography (10% ethyl acetate in heptane)to give 4-(4′-bromophenylsulfanyl)-2-tert-Butoxycarbonylaminobutryicacid methyl ester (1.37 g, 100%) as solid. ¹H NMR (CDCl₃), δ 7.38 (d,J=12 Hz, 2H), 7.18 (d, J=12 Hz, 2H), 5.08 (d, J=8 Hz, 1H), 4.43 (m, 1H),3.73 (s, 3H), 2.92 (m, 2H), 2.21 (m, 2H), 1.45 (s, 9H).

[0541] 2.2-tert-Butoxycarbonylamino-4-(4′-dibenzofuan-4-yl-biphenyl-4-ylsulfanyl)-butryicacid methyl ester

[0542] A solution of4-(4′-bromophen-4-ylsulfanyl)-2-tert-butoxycarbonylaminobutyric acidmethyl ester (404 mg, 1 mmol), (4-Dibenzofuran-4-yl-phenyl)boronic acid(302 mg, 1.05 mmol), Pd(PPh₃)₄ (52 mg, 5% mol) in toluene (10 mL) andethanol (3 mL) was heated until the solution became clear andsubsequently treated with 2 M K₂CO₃ (1.5 mL). The reaction mixture washeated to reflux for 2 h, cooled to room temperature, diluted with ethylacetate (100 mL). The organic layer was washed successively with sat. aqNH₄Cl and sat. aq NaCl, dried over MgSO₄ and concentrated. Purificationby flash column chromatography (2-10% ethyl acetate in heptane) to give2-tert-Butoxycarbonylamino-4-(4′-dibenzofuan-4-yl-biphenyl-4-ylsulfanyl)-butryicacid methyl ester (340 mg, 60%) as white solid. ¹H NMR (CDCl₃), 7.95 (m,4H), 7.75 (m, 2H), 7.62 (m, 4H), 7.41 (m, 5H), 5.11 (d, J=12 Hz, 1H),4.47 (m, 1H), ), 3.78 (s, 3H), 3.01 (t, J=8 Hz, 2H), 2.24 (m, 1H), 2.01(m, 1H), 1.45 (s, 9H). LCMS 569 (M⁺+1).

[0543] 3.2-tert-Butoxycarbonylamino-4-(4′-dibenzofuan-4-yl-biphenyl-4-ylsulfanyl)-butryicAcid

[0544] A solution of2-tert-Butoxycarbonylamino-4-(4′-dibenzofuan-4-yl-biphenyl-4-ylsulfanyl)butryicacid methyl ester (190 mg, 0.335 mmol) in THF (2 mL) and methanol (2 mL)was cooled to 0° C. and treated with 2 N KOH (1.25 mL). After stirring 1h, the solution was quenched with 10% HCl (to pH 2) and diluted withethyl acetate (25 mL). After organic layer was seperated the aqueouslayer was extracted with ethyl acetate (3×15 mL) and the combinedorganic layers were dried over MgSO₄ and concentrated. Purification byflash column chromatography (2-5% methanol in dichloromethane) gave2-tert-Butoxycarbonylamino-4-(4′-dibenzofuan-4-yl-biphenyl-4-ylsulfanyl)-butryicacid (180 mg, 97%) as pale solid. ¹H NMR (DMSO), 8.15 (dd, J=7, 12 Hz,2H), 7.98 (d, J=9 Hz, 2H), 7.83 (d, J=9, 2H), 7.69 (d J=9 Hz, 4H), 7.47(m, 5H), 7.23 (d, J=8 Hz, 1H), 4.07 (m, 1H), 3.01 (m, 2H), 1.95 (m, 2H),1.37 (s, 9H). LCMS 554 (M⁺+1).

Example 122

[0545]2-tert-Butoxycarbonylamino-5-(4′-dibenzofuran-4-yl-biphen-4-yl)-5-pentenoicAcid

[0546] 1. 2-tert-Butoxycarbonylamino-5-pentenoic Acid Methyl Ester

[0547] A solution of di-tert-butyl dicarbonate (11.4 g, 52.1 mmol) in1,4-dioxane (15 mL) was slowly added to a second solution of2-amino-5-pentenoic acid (5 g, 43.4 mmol) in 1 N NaOH (55 mL) at 0° C.After stirring for 16 h, the solution was acidified with 5% HCl to pH 2,and the resulting mixture was extracted with ethyl acetate (3×80 mL).The combined organic layers were dried over MgSO₄ and concentrated. Theresulting residue was dissolved in DMF (50 mL) and treated with K₂CO₃ (7g, 51 mmol). After stirring for 15 min, the solution was cooled to 0° C.and treated with iodomethane (3.4 mL, 51 mmol). After the addition wascomplete, the reaction mixture was stirred at room temperature foranother 4 h, filtered and the resulting solid was washed with ethylacetate (200 mL). The filtrate was washed successively with 5% aq HCl,sat. aq NaCl, dried over MgSO₄ and concented. Purification by flashcolumn chromatography (5% ethyl acetate in heptane) provided2-tert-Butoxycarbonylamino-5-pentenoic acid methyl ester (9.03 g, 94%)as an oil. ¹HNMR (CDCl₃), δ 5.73 (m, 1H), 5.12 (m, 1H), 5.03 (m, 1H),4.38 (dd, J=6, 12 Hz, 1H), 3.74 (s, 3H), 2.51 (m, 2H), 1.46 (s, 9H).

[0548] 2. 5-(4-Bromophenyl)-2-tert-butoxycarbonylamino-5-pentenoic AcidMethyl Ester

[0549] A sealed tube charged with 4-bromoiodobenzene (2.83 g, 10 mmol),2-tert-butoxycarbonylamino-5-pentenoic acid methyl ester (2.52 g, 11mmol), triethylamine (1.55 mL, 11 mmol) and Pd(OAc)₂ (90 mg, 4 mol %) inacetonitrile (2 mL) was degased with nitrogen, sealed and heated at 100°C. for 16 h. After cooling, the reaction mixture was flitered throughcelite and concentrated. Purification by flash column chromatography(10% ethyl acetate in heptane) gave5-(4-Bromophenyl)-2-tert-butoxycarbonylamino-5-pentenoic acid methylester (2.61 g, 69%) as an oil. ¹H NMR (CDCl₃), δ 7.40 (m, 2H), 7.20 (m,2H), 6.38 (d, J=15 Hz, 1H), 6.06 (ddd, J=8, 8, 15 Hz, 1H), 5.08 (d, J=8Hz, 1H), 4.45 (m, 1H), 3. 76 (s, 3H), 2.67 (m, 2H), 1.45 (s, 9H).

[0550] 3.2-tert-Butoxycarbonylamino-5-(4′-dibenzofuran-4-yl-biphen-4-yl)-5-pentenoicAcid Methyl Ester

[0551] A solution of5-(4-bromophenyl)-2-tert-butoxycarbonylamino-5-pentenoic acid methylester (0.384 g, 1 mmol), 4-(4-dibenzofuranyl)benzeneboronic acid (0.302g, 1.05 mmol) and Pd(PPh₃)₄ (0.052 g, 5% mol) in toluene (10 mL) andethanol (2.5 mL) was heated until the solution became clear andsubsequently treated with 2 M K₂CO₃ (1.5 mL). The reaction mixture washeated to reflux for 2 h, cooled to room temperature, diluted with ethylacetate (100 mL). The organic layer was washed successively with 2% aqHCl and sat. aq NaCl, dried over MgSO₄ and concentrated. Purification byflash column chromatography (2-10% ethyl acetate in heptane) gave2-tert-Butoxycarbonylamino-5-(4′-dibenzofuran-4-yl-biphen-4-yl)-5-pentenoicacid methyl ester (422 mg, 77%) as a oil. ¹H NMR (CDCl₃), δ 7.98 (d, J=9Hz, 2H), 7.94 (d, J=8 Hz, 2H), 7.76 (d, J=8 Hz, 2H), 7.66 (m, 4H), 7.42(m, 5H), 6.53 (d, J=15 Hz, 1H), 6.14 (ddd, J=8, 8, 15 Hz, 1H), 5.11 (d,J=8 Hz, 1H), 4.84 (m, 1H), 3.79 (s, 3H), 2.72 (m, 2H), 1.52 (s, 9H).LCMS 448 (M⁺−100).

[0552] 4.2-tert-Butoxycarbonylamino-5-(4′-dibenzofuran-4-yl-biphen-4-yl)-5-pentenoicAcid

[0553] A solution of2-tert-butoxycarbonylamino-5-(4′-dibenzofuran-4-yl-biphen-4-yl)-5-pentenoicacid methyl ester (0.2 g, 0.365 mmol) in THF (2 mL) and methanol (2 mL)was cooled to 0° C. and treated with 2 N KOH (1.0 mL). After stirring atroom temperature for 1 h the solution was acidified with 10% HCl to pH 2and diluted with 25 ml of ethyl acetate. After being seperated, theaqueous layer was extracted with ethyl acetate (3×15 mL) and thecombined organic layers were dried over MgSO₄ and concentrated.Purification by flash column chromatography (2-5% methanol indichloromethane) provided2-tert-Butoxycarbonylamino-5-(4′-dibenzofuran-4-yl-biphen-4-yl)-5-pentenoicacid (160 mg, 82%) as white solid. MP 180-182° C.; ¹H NMR (CDCl₃), §7.90 (d, J=9 Hz, 2H), 7.84 (d, J=8 Hz, 2H), 7.67 (d, J=9 Hz, 2H), 7.55(m, 4H), 7.32 (m, 5H), 6.50 (d, J=15 Hz, 1H), 6.12 (ddd, J=8, 8, 15 Hz,1H), 5.01 (d, J=8 Hz, 1H), 4.4 (m, 1H), 2.72 (m, 2H), 1.38 (s, 9H). LCMS434 (M⁺−100).

Example 123

[0554]2-tert-Butoxycarbonylamino-5-(4′-dibenzofuran-4-yl-biphen-4-yl)-pentanoicAcid

[0555] 1.2-tert-Butoxycarbonylamino-5-(4′-dibenzofuran-4-yl-biphen-4-yl)-pentanoicacid methyl ester

[0556] A solution of2-tert-Butoxycarbonylamino-5-(4′-dibenzofuran-4-yl-biphen-4-yl)-5-pentenoicacid methyl ester (0.225 g, 0.5 mmol) and 10% Pd/C (25 mg, 5 mol %) inethyl acetate (15 mL) was hydrogenated in a Parr apperatous at 20 psifor 1 h. After the reaction was complete, the solution was filtered andthe solid was washed with ethyl acetate (50 mL), dried over MgSO₄ andconcentrated. Purification by flash column chromatography (5% ethylacetate in heptane) gave2-tert-Butoxycarbonylamino-5-(4′-dibenzofuran-4-yl-biphen-4-yl)-pentanoicacid methyl ester (222 mg, 98%) as a foam. ¹H NMR (CDCl₃), δ 7.98 (d,J=9 Hz, 2H), 7.95 (d, J=8 Hz, 2H), 7.75 (d, J=9 Hz, 2H), 7.63 (m, 4H),7.37 (m, 5H), 5.01 (d, J=9 Hz, 1H), 4.38 (m, 1H), 3.71 (s, 3H), 2.72 (m,2H), 1.80 (m, 4H), 1.46 (s, 9H). LCMS 450 (M⁺−100).

[0557] 2.2-tert-Butoxycarbonylamino-5-(4′-dibenzofuran-4-yl-biphen-4-yl)-pentanoicAcid

[0558] A solution of2-tert-butoxycarbonylamino-5-(4′-dibenzofuran-4-yl-biphen-4-yl)-5-pentanoicacid methyl ester (250 mg, 0.454 mmol) in THF (2 mL) and methanol (2 mL)was cooled to 0° C. and treated with 2 N KOH (1.0 mL). After stirring atroom temperature for 1 h the solution was acidified with 10% HCl to pH 2and diluted with 25 ml of ethyl acetate. After being seperated, theaqueous layer was extracted with ethyl acetate (3×15 mL) and thecombined organic layers were dried over MgSO₄ and concentrated.Purification by flash column chromatography (2-5% methanol indichloromethane) provided the desired product (210 mg, 87%) as a whitesolid. ¹H NMR (CDCl₃), 7.98 (d, J=9 Hz, 2H), 7.94 (d, J=8 Hz, 2H), 7.74(d, J=9, 2H), 7.62 (m, 4H), 7.41 (m, 5H), 5.01 (d, J=9 Hz, 1H), 4.39 (m,1H), 2.72 (m, 2H), 1.85 9m, 4H), 1.47 (s, 9H). LCMS 436 (M⁺−100).

Example 124

[0559]2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-yl)-propanoicAcid

[0560] 1. 2-tert-Butoxycarbonylamino-3-(4-iodophenyl)-propanoic AcidMethyl Ester

[0561] A solution of2-tert-butoxycarbonylamino-3-(4-iodophenyl)-propanoic acid (5.0 g, 12.8mmol) in DMF (50 mL) was treated with K₂CO₃ (2.2 g, 15.4 mmol). Afterstirring for 15 min, the solution was cooled to 0° C. and treated withiodomethane (1.0 mL, 15.4 mmol). After the addition was complete, thereaction mixture was stirred at room temperature for another 16 h,filtered and the resulting solid was washed with ethyl acetate (200 mL).The filtrate was washed successively with 5% aq HCl, sat. aq NaCl, driedover MgSO₄ and concented. Purification by flash column chromatography(5% ethyl acetate in heptane) provided the desired product (5.74 g, 98%)as an oil. ¹H NMR (CDCl₃), δ 7.61 (d, J=9 Hz, 2H), 7.74 (d, J=9, 2H),4.97 (d, J=7 Hz, 1H), 4.56 (m, 1H), 3.73 (s, 3H), 3.02 (ddd, J=7, 7, 12Hz, 2H), 1.47 (s, 9H).

[0562] 2.2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-yl)-propanoicAcid Methyl Ester

[0563] A solution of2-tert-Butoxycarbonylamino-3-(4-iodophenyl)-propanoic acid methyl ester(1.22 g, 3 mmol), 4-(4-dibenzofuranyl)benzeneboronic acid (0.906 g, 3.15mmol) and Pd(PPh₃)₄ (160 mg, 5 mol %) in toluene (25 mL) and ethanol(6.0 mL) was treated with 2 M K₂CO₃ (4.5 mL). The reaction mixture washeated to reflux for 2 h, cooled to room temperature, diluted with ethylacetate (100 mL). The organic layer was washed successively with 2% aqHCl and sat. aq NaCl, dried over MgSO₄ and concentrated. Purification byflash column chromatography (2-10% ethyl acetate in heptane) gave2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-yl)-propanoicacid methyl ester (1.1 g, 70%) as an oil. ¹H NMR (CDCl₃), δ 7.98 (d, J=9Hz, 2H), 7.96 (d, J=8 Hz, 2H), 7.74 (d, J=9, 2H), 7.66 (m, 4H), 7.42 (m,5H), 5.04 (d, J=9 Hz, 1H), 4.66 (m, 1H), 3.73 (s, 3H), 3.15 (m, 2H),1.57 (s, 9H). LCMS 422 (M⁺−100).

[0564] 3.2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-yl)-propanoicAcid

[0565] A solution of2-tert-butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-yl)-propanoicacid methyl ester (125 mg, 0.24 mmol) in THF (2 mL) and methanol (2 mL)was cooled to 0° C. and treated with 2 N KOH (1.0 mL). After stirring atroom temperature for 1 h the solution was acidified with 10% HCl to pH 2and diluted with ethyl acetate (25 mL). After being seperated, theaqueous layer was extracted with ethyl acetate (3×15 mL) and thecombined organic layers were dried over MgSO₄ and concentrated.Purification by flash column chromatography (2-5% methanol indichloromethane) provided2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-yl)-propanoicacid (80 mg, 67%) as white solid. ¹H NMR (CDCl₃), 7.98 (d, J=9 Hz, 2H),7.93 (d, J=8 Hz, 2H), 7.74 (d, J=9, 2H), 7.59 (m, 4H), 7.41 (m, 5H),5.01 (d, J=8 Hz, 1H), 4.66 (m, 1H), 3.30 (m, 2H), 1.47 (s, 9H). LCMS 408(M⁺−100).

Example 125

[0566]2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-ylsulfanyl)-propanoicAcid

[0567] 1. 2-tert-Butoxycarbonylamino-3-methylsulfonylpropanoic AcidMethyl Ester

[0568] A solution of N-tert-butoxycarbonylserine (1.1 g, 5.0 mmol) andtriethylamine (0.84 mL, 6.0 mmol) in dichloromethane (50 mL) was cooledto 0° C. and treated with methylsulfonyl chloride (0.44 mL, 5.8 mmol)).After stirring an additional 2 h, the reaction mixture was acidifiedwith 2% HCl (20 mL) and extracted with dichloromethane (3×20 mL). Thecombined organic layers were washed successively with sat. aq NaHCO₃,and sat. aq NaCl, dried over MgSO₄ and concentrated. Purification byflash column chromatography (5% ethyl acetate in heptane) gave thedesired product (1.25 g, 84%) as an oil. ¹H NMR (CDCl₃), 5.71 (d, J=7Hz, 1H), 4.56 (m, 3H), 3.82 (s, 3H), 3.02 (s, 3H), 1.44 (s, 9H)

[0569] 2. 2-tert-Butoxycarbonylamino-3-(4-bromophenylsulfanyl)-propanoicAcid Methyl Ester

[0570] Solution of 2-tert-Butoxycarbonylamino-3-methylsulfonylpropanoicacid methyl ester (0.86 g, 2.89 mmol) and 4-bromobenzenthiol (0.56 g,2.89 mmol) in DMF (10 mL) was cooled to at 0° C. and treated with Cs₂CO₃(1.1 g, 3.2 mmol). After stirring at room temperature for 2 h, thereaction was acidified with 5% HCl (15 mL) and diluted with ethylacetate (25 mL). After separation, the aqueous layer was extracted withethyl acetate (3×15 mL) and the combined organic layers were washed withsat. aq NaCl, dried over MgSO₄, filtered, and concentrated. Purificationby flash column chromatography (5% ethyl acetate in heptane) gave thedesired product (857 mg, 76%) as a white solid. ¹H NMR (CDCl₃), δ 7.40(d, J=9 Hz, 2H), 7.27 (d, J=9, 2H), 5.30 (d, J=7 Hz, 1H), 4.56 (m, 1H),3.59 (s, 3H), 3.35 (ddd, J=7, 7, 12 Hz, 2H), 1.47 (s, 9H).

[0571] 3.2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-ylsulfanyl)-propanoicAcid Methyl Ester

[0572] A solution of2-tert-Butoxycarbonylamino-3-(4-bromophenylsulfanyl)-propanoic acidmethyl ester (0.55 g, 1.41 mmol), 4-(4-dibenzofuranyl)benzeneboronicacid (0.44 g, 1.52 mmol) and Pd(PPh₃)₄ (0.073 g, 5 mol %) in toluene (15mL) and ethanol (3.0 mL) was treated with 2 M K₂CO₃ (2.2 mL). Thereaction mixture was heated to reflux for 2 h, cooled to roomtemperature, diluted with ethyl acetate (100 mL). The organic layer waswashed successively with 2% aq HCl and sat. aq NaCl, dried over MgSO₄and concentrated. Purification by flash column chromatography (2-10%ethyl acetate in heptane) gave the desired product (552 mg, 72%) as awhite solid. ¹H NMR (CDCl₃), δ 8.01 (d, J=6 Hz, 2H), 7.96 (dd, J=4 Hz, 8Hz, 2H), 7.74 (d, J=9 Hz, 2H), 7.66 (m, 4H), 7.42 (m, 5H), 5.41 (d, J=7Hz, 1H), 4.62 (m, 1H), 3.73 (s, 3H), 3.45 (d, J=4 Hz, 2H), 1.57 (s, 9H).LCMS 454 (M⁺−100).

[0573] 4.2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-ylsulfanyl)-propanoicAcid

[0574] A solution of2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-ylsulfanyl)-propanoicacid methyl ester (0.150 g, 0.27 mmol) in THF (2 mL) and methanol (2 mL)was cooled to 0° C. and treated with 2 N KOH (1.0 mL). After stirring atroom temperature for 1 h the solution was acidified with 10% HCl to pH 2and diluted with ethyl acetate (25 mL). After being seperated, theaqueous layer was extracted with ethyl acetate (3×15 mL) and thecombined organic layers were dried over MgSO₄ and concentrated.Purification by flash column chromatography (2-5% methanol indichloromethane) provided2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-ylsulfanyl)-propanoicacid (110 mg, 75%) as white solid. ¹H NMR (CDCl₃), δ 8.18 (d, J=7 Hz,2H), 8.14 (dd, J=1, 7 Hz, 2H), 7.98 (d, J=9 Hz, 2H), 7.82 (d, J=9 Hz,2H), 7.72 (m, 4H), 7.51 (m, 3H), 3.90 (m, 1H), 3.48 (dd, J=4, 12 Hz,1H), 3.30 (m, 1H), 1.47 (s, 9H). LCMS 440 (M⁺−100).

Example 126

[0575]2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-ylmethylsulfanyl)-3,3-dimethylpropanoicAcid

[0576] 1.2-tert-butoxycarbonylamino-3-(4-bromophenylmethylsulfanyl)-3,3-dimethylpropanoicAcid Methyl Ester

[0577] A solution of 4-bromobenzyl alcohol (1.87 g, 10 mmol) in CF₃CO₂H(19 mL) and CF₃SO₃H (1 mL) was treated with pencilamine (1.49 g, 10mmol). The reaction mixture was stirred for another 4 h thenconcentrated. The resulting residue was dissolved in 2 M NaOH (20 mL),cooled to 0° C. and treated with a second solution of di-tert-butyldicarbonate in 1,4-dioxane (10 mL) in a dropwise manner. After stirringfor 16 h 3 N HCl was added until the solution became pH 2 and theresulting solution was extracted with ethyl acetate (3×50 mL). Thecombined organic layers were washed with sat. aq NaCl, dried over MgSO₄and concentrated. The remaining residue was dissolved in DMF (15 mL) andtreated with K₂CO₃ (2 g, 14.4 mmol) and MeI (1 mL, 16 mmol). After theaddition was complete, the reaction mixture was stirred for 16 h andfiltered to remove solid, which was washed by ethyl acetate (200 mL).The filtrate was washed with sat. aq NaCl, dried over MgSO₄ andconcentrated. Purification by flash column chromatography (10% ethylacetate in heptane) provided the desired product (2.5 g, 58%, 3 steps)as an oil. ¹H NMR (CDCl₃), δ 7.43 (d, J=8 Hz, 2H), 7.18 (d, J=8 Hz, 2H),5.36 (d, J=7 Hz, 1H), 4.35 (dd, J=9, 30 Hz, 1H), 3.75 (m, 5H), 1.36 (s,9H)

[0578] 2.2-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-ylmethylsulfanyl)-3,3-dimethylpropanoicAcid Methyl Ester

[0579] A solution of2-tert-butoxycarbonylamino-3-(4-bromophenylmethylsulfanyl)-3,3-dimethylpropanoicacid methyl ester (0.432 g, 1 mmol), 4-(4-dibenzofuranyl)benzeneboronicacid (0.305 g, 1.05 mmol) and Pd(PPh₃)₄ (0.052 g, 5 mol %) in toluene(10 mL) and ethanol (3.0 mL) was treated with 2 M K₂CO₃ (1.5 mL). Thereaction mixture was heated to reflux for 2 h, cooled to roomtemperature, diluted with ethyl acetate (100 mL). The organic layer waswashed successively with 2% aq HCl and sat. aq NaCl, dried over MgSO₄and concentrated. Purification by flash column chromatography (2-10%ethyl acetate in heptane) gave the desired product (430 mg, 72%) as anoil. ¹H NMR (CDCl₃), δ 8.01 (d, J=8 Hz, 2H), 7.94 (d, J=8 Hz, 2H), 7.78(d, J=8 Hz, 2H), 7.66 (m, 4H), 7.42 (m, 5H), 5.44 (d, J=9 Hz, 1H), 4.46(d, J=9 Hz, 1H), 3.87 (s, 2H), 3.81 (s, 3H), 1.44 (s, 9H). LCMS 618(M⁺+23).

[0580] 3.2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-ylmethylsulfanyl)-3,3-dimethylpropanoicAcid

[0581] A solution of2-tert-butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-yl)-propanoicacid methyl ester (0.250 g, 0.42 mmol) in THF (2 mL) and methanol (2 mL)was cooled to 0° C. and treated with 2 N KOH (1.0 mL). After stirring atroom temperature for 1 h the solution was acidified with 10% HCl to pH 2and diluted with ethyl acetate (25 mL). After being seperated, theaqueous layer was extracted with ethyl acetate (3×15 mL) and thecombined organic layers were dried over MgSO₄ and concentrated.Purification by flash column chromatography (2-5% methanol indichloromethane) provided the desired product (160 mg, 66%) as a whitesolid. ¹H NMR (CDCl₃), δ 8.01 (d, J=8 Hz, 2H), 7.94 (d, J=8 Hz, 2H),7.78 (d, J=8 Hz, 2H), 7.66 (m, 4H), 7.42 (m, 5H), 5.44 (d, J=9 Hz, 1H),4.46 (d, J=9 Hz, 1H), 3.90 (m, 2H), 1.44 (s, 9H). LCMS 6041′ (M⁺+23)

Example 127

[0582]2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-ylmethoxy)propanoicAcid

[0583] 1. Aziridine-N-butoxycarbonyl-2-carboxylic Acid Methyl Ester

[0584] A solution of aziridine-2-carboxylic acid methyl ester (1.5 g, 15mmol) in THF (50 mL) was treated with Boc anhydride (3.9 g, 18 mmol) andDMAP (100 mg). After stirring for 16 h the reaction mixture was filteredthrough a short pad of silica gel which was subsequently washed withethyl acetate (200 mL). The filtrate was concentrated to give crudeaziridine-N-butoxycarbonyl-2-carboxylic acid methyl ester as oil. ¹H NMR(CDCl₃), 3.77 (s, 3H), 3.03 (dd, J=3, 8 Hz, 1H), 2.52 (dd, J=1, 3 z,1H), 2.41 (dd, J=1, 8 Hz, 1H), 1.45 (s, 9H).

[0585] 2. 2-tert-butoxycarbonyl-3-(4-bromophen-4-ylmethoxy)propanoicAcid Methyl Ester

[0586] A solution of 4-bromobenyl alcohol (3.7 g, 20 mmol) in toluene(15 mL) was treated with BF₃ OEt₂ (150 mL). After stirring 15 min,aziridine-N-tert-butoxy-carbonyl-2-carboxylic acid methyl ester (2 g, 10mmol) was added and stirring was continued for 16 h. Once complete, thesolution was diluted with ethyl acetate (100 mL) and washed with sat.aqNaCl, dried over MgSO₄ and concentrated. Purification by flash columnchromatography (2-10% ethyl acetate in heptane) provided the desiredproduct (1.2 g, 31%) as a white solid. ¹H NMR (CDCl₃), δ 7.43 (d, J=8Hz, 2H), 7.18 (d, J=8 Hz, 2H), 5.36 (d, J=9 Hz, 1H), 4.47 (m, 3H), 3.86(dd, J=1, 6 Hz, 1H), 3.75 (s, 3H), 3.66 (dd, J=1, 6 Hz, 1H), 1.45 (s,9H).

[0587] 3.2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-ylmethyloxy)-propanoicAcid Methyl Ester

[0588] A solution of2-tert-butoxycarbonyl-3-(4-bromophen-4-ylmethoxy)propanoic acid methylester (0.388 g, 1 mmol), 4-(4-dibenzofuranyl)benzeneboronic acid (0.305g, 1.05 mmol) and Pd(PPh₃)₄ (0.052 g, 5% mol) in toluene (10 mL) andethanol (3.0 mL) was treated with 2 M K₂CO₃ (1.5 mL). The reactionmixture was heated to reflux for 2 h, cooled to room temperature,diluted with ethyl acetate (100 mL). The organic layer was washedsuccessively with 2% aq HCl and sat. aq NaCl, dried over MgSO₄ andconcentrated. Purification by flash column chromatography (2-10% ethylacetate in heptane) gave the desired product (369 mg, 67%) as an oil. ¹HNMR (CDCl₃), δ 8.01 (d, J=8 Hz, 2H), 7.94 (d, J=8 Hz, 2H), 7.78 (d, J=8Hz, 2H), 7.66 (m, 4H), 7.42 (m, 5H), 5.44 (d, J=9 Hz, 1H), 4.58 (dd,J=9, 21 Hz, 2H), 4.05 (m, 1H), 3.93 (dd, J=1, 6 Hz, 1H), 3.78 (m, 4H),1.44 (s, 9H). LCMS 574 (M⁺+23).

[0589] 4.2-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-ylmethyloxy)-propanoicAcid

[0590] A solution of2-tert-butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-yl)-propanoicacid methyl ester (0.125 g, 0.24 mmol) in THF (2 mL) and methanol (2 mL)was cooled to 0° C. and treated with 2 N KOH (1.0 mL). After stirring atroom temperature for 1 h the solution was acidified with 10% HCl to pH 2and diluted with ethyl acetate (25 mL). After being seperated, theaqueous layer was extracted with ethyl acetate (3×15 mL) and thecombined organic layers were dried over MgSO₄ and concentrated.Purification by flash column chromatography (2-5% methanol indichloromethane) provided the desired product (80 mg, 67%) as a whitesolid. ¹H NMR (CDCl₃), δ 8.01 (d, J=8 Hz, 2H), 7.94 (d, J=8 Hz, 2H),7.78 (d, J=8 Hz, 2H), 7.66 (m, 4H), 7.42 (m, 5H), 5.44 (d, J=9 Hz, 1H),4.62 (s, 2H), 4.53 (m, 1H), 4.02 (dd, J=1, 6 Hz, 1H), 3.78 (dd, J=1, 6Hz, 1H), 1.44 (s, 9H). LCMS 560 (M⁺+23).

Example 128

[0591]2-Benzyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)phenyl]-benzofuran

[0592] A solution of bis-(pinacolato)diboron (2.64 g, 10.41 mmol) inanhydrous DMSO (20 mL) was added to a stirred suspension of the knowntriflate, trifluoromethanesulfonic acid-4-(2-benzylbenzofuran-3yl)phenyl ester, (4.09 g, 9.47 mmol) and potassium acetate (3.71 g, 37.9mmol) in anhydrous DMSO (20 mL).[1,1′-bis-(Diphenylphosphino)-ferrocene]dichloropalladium(II)-DCMcomplex (770 mg, 0.95 mmol) was added as a solid, and the resultingsuspension was heated to 80° C. for 4 hrs. The reaction mixture wascooled to room temperature, diluted with diethyl ether (150 mL), washedwith water (2×50 mL), brine (3×50 mL), dried over anhydrous MgSO₄,filtered and concentrated in vacuo. Purification of the product by flashcolumn chromatography, using 10% ethyl acetate/heptane as eluent,afforded the title compound as a white solid (2.96 g).

Example 129

[0593] Additional compounds of formula I, which can be preparedessentially according to the methods and procedures set forth above,include the following.

[0594] Compnd No. Compound Name

[0595] 1S-[4′-(2-benzyl-1-benzofuran-3-yl)-6-fluoro-4-nitrobiphenyl-3-yl]-N-(tert-butoxycarbonyl)-L-cysteine;

[0596] 2S-[4′-(2-benzyl-1-benzofuran-3-yl)-3-nitrobiphenyl-4-yl]-N-(tert-butoxycarbonyl)-L-cysteine;

[0597] 3S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-(tert-butoxycarbonyl)-L-cysteine;

[0598] 43-({[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}sulfinyl)-N-(tert-butoxycarbonyl)-L-alanine;

[0599] 53-({[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}sulfonyl)-N-(tert-butoxycarbonyl)-L-alanine;

[0600] 6N-benzoyl-S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-L-cysteine;

[0601] 7S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-(3-phenylpropanoyl)-L-cysteine;

[0602] 8N-(1H-benzimidazol-5-ylcarbonyl)-S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-L-cysteine;

[0603] 9S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-[(4-fluorophenyl)acetyl]-L-cysteine;

[0604] 10S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-[(3-nitrophenyl)acetyl]-L-cysteine;

[0605] 11S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-(phenylacetyl)-L-cysteine;

[0606] 12S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-(1H-indol-5-ylcarbonyl)-L-cysteine;

[0607] 13S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-[(4-nitrophenyl)acetyl]-L-cysteine;

[0608] 14S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-[(2-nitrophenyl)acetyl]-L-cysteine;

[0609] 15S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-[(4-hydroxyphenyl)acetyl]-L-cysteine;

[0610] 16N-acetyl-S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-L-cysteine;

[0611] 17S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-[(4-methoxyphenyl)acetyl]-L-cysteine;

[0612] 18N-[(4-aminophenyl)acetyl]-S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-L-cysteine;

[0613] 19N-(tert-butoxycarbonyl)-S-{[4′-(1H-indol-1-yl)biphenyl-4-yl]methyl}-L-cysteine;

[0614] 20N-(tert-butoxycarbonyl)-3-({[4′-(1H-indol-1-yl)biphenyl-4-yl]methyl}sulfinyl)-L-alanine;

[0615] 213-({[4′-(1H-indol-1-yl)biphenyl-4-yl]methyl}sulfinyl)-N-(phenylacetyl)-L-alanine;

[0616] 22S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-(2-methyl-1,3-thiazol-4-yl)-L-cysteine;

[0617] 23S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-[(4-methyl-3-nitrophenyl)sulfonyl]-L-cysteine;

[0618] 24S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-(methoxycarbonyl)-L-cysteine;

[0619] 25S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-(isobutoxycarbonyl)-L-cysteine;

[0620] 26S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-(morpholin-4-ylcarbonyl)-L-cysteine;

[0621] 27S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-[(dimethylamino)carbonyl]-L-cysteine;

[0622] 28S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-[(benzyloxy)carbonyl]-L-cysteine;

[0623] 29N-(tert-butoxycarbonyl)-3-({4-[(1H-indol-1-ylacetyl)amino]benzyl}sulfonyl)-D-alanine;

[0624] 303-{[4-({[5-(benzyloxy)-1H-indol-1-yl]acetyl}amino)benzyl]sulfonyl}-N-(tert-butoxycarbonyl)-D-alanine;

[0625] 31S-{[4′-(1H-indol-1-yl)biphenyl-4-yl]methyl}-N-(methoxycarbonyl)-L-cysteine;

[0626] 32S-{[4′-(1H-indol-1-yl)biphenyl-4-yl]methyl}-N-(isobutoxycarbonyl)-L-cysteine;

[0627] 33S-{[4′-(1H-indol-1-yl)biphenyl-4-yl]methyl}-N-(morpholin-4-ylcarbonyl)-L-cysteine;

[0628] 34 methylS-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-(phenylacetyl)-L-cysteinate;

[0629] 35 methylS-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-(3-phenylpropanoyl)-L-cysteinate;

[0630] 36S-{[4′-(1H-indol-1-yl)biphenyl-4-yl]methyl}-N-[(3-nitrophenyl)acetyl]-L-cysteine;

[0631] 37S-{[4′-(1H-indol-1-yl)biphenyl-4-yl]methyl}-N-(phenylacetyl)-L-cysteine;

[0632] 38N-[(dimethylamino)carbonyl]-S-{[4′-(1H-indol-1-yl)biphenyl-4-yl]methyl}-L-cysteine;

[0633] 393-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-2-[(pyridine-3-carbonyl)-amino]-propionicacid;

[0634] 40N-(tert-butoxycarbonyl)-3-{[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]sulfonyl}-L-alanine;

[0635] 412-tert-Butoxycarbonylamino-4-(4′-dibenzofuran-4-yl-biphenyl-4-ylsulfanyl)-butyricacid;

[0636] 422-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethanesulfonyl)-propionicacid;

[0637] 432-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-propionicacid;

[0638] 44N-[(benzyloxy)carbonyl]-S-{[4′-(1H-indol-1-yl)biphenyl-4-yl]methyl}-L-cysteine;

[0639] 45N-(tert-butoxycarbonyl)-S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]-L-cysteine;

[0640] 46N-(tert-butoxycarbonyl)-S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]cysteine;

[0641] 47N-(tert-butoxycarbonyl)-3-{[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]sulfinyl}alanine;

[0642] 48N-(tert-butoxycarbonyl)-3-{[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]sulfonyl}alanine;

[0643] 49N-(tert-butoxycarbonyl)-O-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]serine;

[0644] 50N-(tert-butoxycarbonyl)-5-(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)norvaline;

[0645] 51(4E)-2-[(tert-butoxycarbonyl)amino]-5-(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)pent-4-enoicacid;

[0646] 52N-(tert-butoxycarbonyl)-S-(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)homocysteine;

[0647] 532-[(tert-butoxycarbonyl)amino]-4-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)sulfonyl]butanoicacid;

[0648] 54N-(tert-butoxycarbonyl)-O-(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)homoserine;

[0649] 55N-(tert-butoxycarbonyl)-S-(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)cysteine;

[0650] 56N-(tert-butoxycarbonyl)-3-{[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]thio}valine;

[0651] 57N-(tert-butoxycarbonyl)-3-{[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]thio}valine;

[0652] 58N-(tert-butoxycarbonyl)-S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]cysteine;

[0653] 59S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]-N-(3,3-dimethylbutanoyl)cysteine;

[0654] 60N-[(tert-butylamino)carbonyl]-S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]cysteine;

[0655] 61 S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]cysteine;

[0656] 62N-[amino(imino)methyl]-S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]cysteine;

[0657] 63N-{(Z)-[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}-S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]cysteine;

[0658] 64N-benzoyl-S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]cysteine;

[0659] 652-{[(2-{[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]thio}-1-carboxyethyl)amino]carbonyl}benzoicacid;

[0660] 664-[[[1-carboxy-2-[[[4′-(4-dibenzofuranyl)[1,1′-biphenyl]-4-yl]methyl]thio]ethyl]amino]carbonyl]-benzoicacid;

[0661] 67S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]-N-(4-nitrobenzoyl)cysteine;

[0662] 68N-(4-cyanobenzoyl)-S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]cysteine;

[0663] 69S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]-N-(4-fluorobenzoyl)cysteine;

[0664] 70S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]-N-(2,4-difluorobenzoyl)cysteine;

[0665] 71S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]-N-(2,4,6-trifluorobenzoyl)cysteine;

[0666] 72S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]-N-[2-fluoro-4-(trifluoromethyl)benzoyl]cysteine;

[0667] 73S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]-N-[2-fluoro-5-(trifluoromethyl)benzoyl]cysteine;

[0668] 74S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]-N-(4-methoxybenzoyl)cysteine;

[0669] 75S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]-N-(pyridin-3-ylcarbonyl)cysteine;

[0670] 76N-phenylglycyl-S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]cysteine;

[0671] 77S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]-N-{[3-(trifluoromethyl)phenyl]acetyl}cysteine;

[0672] 78S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]-N-[(4-fluorophenyl)acetyl]cysteine;

[0673] 79N-[(1-acetyl-5-hydroxypyrrolidin-3-yl)carbonyl]-S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]cysteine;

[0674] 80N-[(1-acetylpyrrolidin-3-yl)carbonyl]-S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]cysteine;

[0675] 81S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]-N-[(1,5-dimethyl-1H-pyrazol-3-yl)carbonyl]cysteine;

[0676] 824-[(2-{[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]thio}-1-carboxyethyl)amino]-4-oxobutanoicacid;

[0677] 832-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphenyl-3-ylsulfanyl)-propionicacid;

[0678] 842-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-3-fluoro-biphenyl-4-ylmethylsulfanyl)-propionicacid;

[0679] 852-tert-Butoxycarbonylamino-3-[4-(4,6-diphenyl-pyrimidin-2-yl)-benzylsulfanyl]-propionicacid;

[0680] 863-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-2-(4-trifluoromethyl-benzylamino)-propionicacid;

[0681] 873-(2-Acetyl-[1,1′;4′,1″]terphenyl-4″-ylmethylsulfanyl)-2-tert-butoxycarbonylamino-propionicacid;

[0682] 882-tert-Butoxycarbonylamino-3-(2-methoxy-[1,1′;4′,1″]terphenyl-4″-ylmethylsulfanyl)-propionicacid;

[0683] 892-tert-Butoxycarbonylamino-3-(4′-dibenzothiophen-4-yl-biphenyl-4-ylmethylsulfanyl)-propionicacid;

[0684] 902-tert-Butoxycarbonylamino-3-[4-(6-dibenzofuran-4-yl-pyridin-3-yl)-benzylsulfanyl]-propionicacid;

[0685] 912-tert-Butoxycarbonylamino-3-[4-(2-dibenzofuran-4-yl-thiazol-5-yl)-benzylsulfanyl]-propionicacid;

[0686] 922-tert-Butoxycarbonylamino-3-[4-(5-dibenzofuran-4-yl-6-methyl-pyridin-2-yl)-benzylsulfanyl]-propionicacid;

[0687] 932-tert-Butoxycarbonylamino-4-(4′-dibenzofuran-4-yl-biphenyl-4-yloxy)butryicacid;

[0688] 942-tert-Butoxycarbonylamino-4-(4′-dibenzofuan-4-yl-biphenyl-4-ylsulfanyl)-butryicacid;

[0689] 952-tert-Butoxycarbonylamino-4-(4′-dibenzofuan-4-yl-biphenyl-4-ylsulfanyl)-butryicacid methyl ester

[0690] 962-tert-Butoxycarbonylamino-4-(4′-dibenzofuan-4-yl-biphenyl-4-ylsulfanyl)-butryicacid

[0691] 972-tert-Butoxycarbonylamino-5-(4′-dibenzofuran-4-yl-biphen-4-yl)-5-pentenoicacid

[0692] 982-tert-Butoxycarbonylamino-5-(4′-dibenzofuran-4-yl-biphen-4-yl)-5-pentenoicacid methyl ester

[0693] 992-tert-Butoxycarbonylamino-5-(4′-dibenzofuran-4-yl-biphen-4-yl)-5-pentenoicacid

[0694] 1002-tert-Butoxycarbonylamino-5-(4′-dibenzofuran-4-yl-biphen-4-yl)-pentanoicacid

[0695] 1012-tert-Butoxycarbonylamino-5-(4′-dibenzofuran-4-yl-biphen-4-yl)-pentanoicacid methyl ester;

[0696] 1022-tert-Butoxycarbonylamino-5-(4′-dibenzofuran-4-yl-biphen-4-yl)-pentanoicacid;

[0697] 1032-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-yl)-propanoicacid;

[0698] 1042-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-yl)-propanoicacid methyl ester;

[0699] 1052-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-yl)-propanoicacid;

[0700] 1062-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-ylsulfanyl)-propanoicacid;

[0701] 1072-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-ylsulfanyl)-propanoicacid methyl ester;

[0702] 1082-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-ylsulfanyl)-propanoicacid;

[0703] 1092-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-ylmethylsulfanyl)-3,3-dimethylpropanoicacid;

[0704] 1102-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-ylmethylsulfanyl)-3,3-dimethylpropanoicacid methyl ester;

[0705] 1112-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-ylmethoxy)propanoicacid;

[0706] 1122-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-ylmethyloxy)-propanoicacid methyl ester;

[0707] 1132-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-ylmethyloxy)-propanoicacid;

[0708] 1142-Benzyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)phenyl]-benzofuran;

[0709] and pharmaceutically acceptable salts thereof.

Example 130

[0710] Method for Measuring PTP-1B Activity

[0711] The test compounds are evaluated for their in vitro inhibitoryactivity against recombinant human PTP1B with phosphotyrosyldodecapeptide TRDI(P)YETD(P)Y(P)YRK. This corresponds to the 1142-1153insulin receptor kinase regulatory domain, phosphorylated on the 1146,1150 and 1151 tyrosine residues; IR-triphosphopeptide as a source ofsubstrate. Enzyme reaction progression is monitored via the release ofinorganic phosphate as detected by the malachite green—ammoniummolybdate method for the phosphopeptide.

[0712] Preferred compounds of the invention exhibit IC₅₀ values of lessthan 10 μM; more preferred compounds of the invention exhibit IC₅₀values of less than 1 μM. Particularly preferred compounds exhibit IC₅₀values of less than 300 nM.

[0713] All references disclosed herein are hereby incorporated byreference for all purposes.

[0714] The invention and the manner and process of making and using it,are now described in such full, clear, concise and exact terms as toenable any person skilled in the art to which it pertains, to make anduse the same. It is to be understood that the foregoing describespreferred embodiments of the invention and that modifications may bemade therein without departing from the spirit or scope of theinvention.

What is claimed is:
 1. A compound of the formula

and pharmaceutically acceptable salts thereof, wherein R₁ is H, C₁-C₆alkyl, phenyl(C₁-C₆)alkyl, or C₃-C₆ alkenyl; R₆ and R₇ are independentlyH, C₁-C₆ alkyl, aryl(C₁-C₆)alkyl, (C₁-C₈)alkanoyl optionally substitutedwith 1 or 2 groups independently selected from amino, mono ordialkylamino, —NHaryl, —N(C₁-C₆ alkyl)aryl, and CO₂H,aryl(C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl, arylalkoxycarbonyl,heteroarylcarbonyl, heteroaryl, heterocycloalkylcarbonyl, —C(O)NH₂,—C(O)NH(C₁-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, —C(═NH)NH₂,—C(═N—C(O)C₁-C₆ alkoxy)NH—C(O)C₁-C₆ alkoxy, or —SO₂-aryl, wherein thecyclic portions of each of the above are optionally substituted with 1′,2, 3, 4, or 5 groups that are independently halogen, C₁-C₆ alkyl, C₁-C₆alkoxy, NO₂, OH, CO₂H, CN, C₂-C₆ alkanoyl, NH₂, NH(C₁-C₆)alkyl,N(C₁-C₆)alkyl(C₁-C₆)alkyl, haloalkyl or haloalkoxy; R₈ is H,(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkanoyl, wherein the arylgroup is optionally substituted with C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,NO₂, C₁-C₄ haloalkyl, or C₁-C₄ haloalkoxy; R₂₀, R₂₁, R₂₂, and R₂₃ areindependently selected from H, arylalkoxy, arylalkyl, halogen, alkyl,OH, alkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl,NH-aryl, N(C₁-C₄)alkyl-aryl, —NHSO₂-aryl, —N(C₁-C₄alkyl)SO₂aryl, whereinthe aryl group is optionally substituted with 1, 2, 3, or 4 groups thatare independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH, NO₂, C₁-C₄haloalkyl, C₁-C₄ haloalkoxy; L₂ is a bond, —O—(C₁-C₆)alkyl-,—(C₁-C₆)alkyl-O—, —N(R₈)C(O)— (C₁-C₄)alkyl-, —(C₁-C₄)alkyl-C(O)N(R₈)—;L₃ is a bond, —(C₁-C₄)alkyl-O—, —O—(C₁-C₄)alkyl, —(C₁-C₄)alkyl-, —C₂-C₆alkenyl-, —C(O)—, —(C₁-C₄)alkyl-O—, —C(O)NH—, or —NHC(O)—; L₄ is—(C₁-C₆)alkyl-, —S(O)_(u)—(C₁-C₄)alkyl-,—(C₁-C₄)alkyl-S(O)_(u)—(C₁-C₄)alkyl-, —C₂-C₆ alkenyl-, —C₁-C₆alkyl-O—C₁-C₆ alkyl-, —O—C₁-C₆ alkyl-, or C₁-C₆alkyl-O—; wherein u is 0,1, or 2; the A-ring is phenyl, naphthyl, isoindolyl, indolyl, pyridyl,thiazolyl, pyrimidyl, benzofuranyl, benzimidazolyl, or 1H-indazolyl eachof which is optionally substituted with 1, 2, 3, or 4 groups that areindependently, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,C₁-C₄ haloalkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, orN(C₁-C₆)alkyl(C₁-C₆)alkyl; Q is -heteroaryl-(C₁-C₄)alkyl-aryl,-aryl-(C₁-C₄)alkyl-heteroaryl, heteroaryl, or aryl, each of which isoptionally substituted with 1, 2, 3, 4, or 5 groups that areindependently alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, C₁-C₆alkanoyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NH₂, NH(C₁-C₆)alkyl,N(C₁-C₆)alkyl(C₁-C₆)alkyl, phenyl, C₁-C₆ alkanoyl; Q₂ is and H or aryl,wherein the aryl is optionally substituted with 1, 2, or 3 groups thatare independently C₁-C₆ alkyl, C₁-C₆ alkoxy, or halogen; and Y and Y′are independently a bond or —(C₁-C₄)alkyl-.
 2. A compound according toclaim 1, wherein R₆ and R₇ are independently H, C₁-C₆ alkyl,phenyl(C₁-C₆)alkyl, C₁-C₆ alkanoyl optionally substituted with 1 or 2groups independently selected from amino, mono or dialkylamino,—NHphenyl, —N(C₁-C₆ alkyl)aryl, and CO₂H, phenyl(C₁-C₆)alkanoyl,(C₁-C₆)alkoxycarbonyl, benzyloxycarbonyl, benzimidazolylcarbonyl,benzofuranylcarbonyl, furanylcarbonyl, thiazolylcarbonyl,indolylcarbonyl, pyridyl, pyrimidyl, morpholinylcarbonyl,thiomorpholinylcarbonyl, thiomorpholinyl S,S dioxide-carbonyl,piperazinylcarbonyl, piperidinylcarbonyl, pyrrolidinylcarbonyl,pyridylcarbonyl, pyrazolylcarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl,—C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, —C(═NH)NH₂, —C(═N—C(O)C₁-C₄alkoxy)NH—C(O)C₁-C₄ alkoxy, —SO₂-phenyl, or —SO₂-naphthyl wherein thecyclic portions of each of the above are optionally substituted with 1,2, 3, or 4 groups that are independently halogen, C₁-C₆ alkyl, C₁-C₆alkoxy, NO₂, OH, CO₂H, CN, C₁-C₆ alkanoyl, NH₂, NH(C₁-C₆)alkyl,N(C₁-C₆)alkyl(C₁-C₆)alkyl, C₁-C₄ haloalkyl or C₁-C₄ haloalkoxy; and Q is-benzofuranyl-(C₁-C₄)alkyl-phenyl, -pyridyl-(C₁-C₄)alkyl-phenyl,-dibenzofuranyl-(C₁-C₄)alkyl-phenyl, indolyl-(C₁-C₄)alkyl-phenyl,benzo[b]thienyl-(C₁-C₄)alkyl-phenyl, -phenyl-(C₁-C₄)alkyl-benzofuranyl,indolyl, phenyl, benzo[d][1,3]dioxolyl,2,3-dihydrobenzo[b][1,4]dioxinyl, dibenzothienyl, indolinyl,benzofuranyl, benzimidazolyl, or dibenzofuranyl, each of which isoptionally substituted with 1, 2, 3, 4, or 5 groups that areindependently alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, C₁-C₄haloalkyl, C₁-C₄ haloalkoxy, NH₂, NH(C₁-C₆)alkyl,N(C₁-C₆)alkyl(C₁-C₆)alkyl, phenyl or C₁-C₆ alkanoyl; and Q₂ is H orphenyl.
 3. A compound according to claim 2, wherein R₁ is H, C₁-C₆alkyl, benzyl, or allyl; R₂₀, R₂₁, R₂₂, and R₂₃ are independentlyselected from H, benzyloxy, benzyl, halogen, C₁-C₆ alkyl, OH, C₁-C₆alkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, NH-aryl,N(C₁-C₄)alkyl-aryl, —NHSO₂-phenyl, —N(C₁-C₄ alkyl)SO₂phenyl, wherein thephenyl group is optionally substituted with 1, 2, 3, or 4 groups thatare independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH, NO₂, C₁-C₂haloalkyl, C₁-C₂ haloalkoxy; the A-ring is phenyl, naphthyl, pyridyl,thiazolyl, pyrimidyl, isoindolyl, indolyl, benzofuranyl, benzimidazolyl,or 1H-indazolyl each of which is optionally substituted with 1, 2, 3, or4 groups that are independently, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy,C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, orN(C₁-C₆)alkyl(C₁-C₆)alkyl; L₂ is a bond, —O—(C₁-C₆)alkyl-,—(C₁-C₆)alkyl-O—, —N(R₈)C(O)-(C₁-C₄)alkyl-, —(C₁-C₄)alkyl-C(O)N(R₈)—;wherein R₈ is H, (C₁-C₆)alkyl, phenyl(C₁-C₆)alkyl,phenyl(C₁-C₆)alkanoyl, wherein the phenyl groups are optionallysubstituted with C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, NO₂, C₁-C₂haloalkyl, or C₁-C₂ haloalkoxy; and L₃ is a bond, —(C₁-C₄)alkyl-O—,—O—(C₁-C₄)alkyl, —(C₁-C₄)alkyl-, or C(O).
 4. A compound according toclaim 3, wherein the A-ring is isoindolyl, indolyl, benzofuranyl,benzimidazolyl, or 1H-indazolyl each of which is optionally substitutedwith 1, 2, 3, or 4 groups that are independently, halogen, C₁-C₄ alkyl,C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NO₂, NH₂,NH(C₁-C₆)alkyl, or N(C₁-C₆)alkyl(C₁-C₆)alkyl.
 5. A compound according toclaim 3 of the formula

wherein n is 0, 1, 2, 3, or 4; each R₁₀ is independently H, halogen,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NO₂, NH₂,NH(C₁-C₆)alkyl, or N(C₁-C₆)alkyl(C₁-C₆)alkyl; Q is-benzofuranyl-(C₁-C₄)alkyl-phenyl, -pyridyl-(C₁-C₄)alkyl-phenyl,-dibenzofuranyl-(C₁-C₄)alkyl-phenyl, indolyl-(C₁-C₄)alkyl-phenyl,-phenyl-(C₁-C₄)alkyl-benzofuranyl, indolyl, phenyl, indolinyl,benzofuranyl, benzimidazolyl, or dibenzofuranyl, each of which isoptionally substituted with 1, 2, 3, 4, or 5 groups that areindependently C₁-C₆ alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, NH₂, NH(C₁-C₆)alkyl,N(C₁-C₆)alkyl(C₁-C₆)alkyl, or phenyl.
 6. A compound according to claim5, wherein R₁ is H, C₁-C₆ alkyl, or benzyl, R₆ and R₇ are independentlyH, C₁-C₆ alkyl, phenyl(C₁-C₆)alkyl, (C₂-C₆)alkanoyl,phenyl(C₁-C₆)alkanoyl, (C₁-C₆) alkoxycarbonyl, benzyloxycarbonyl,benzimidazolylcarbonyl, benzofuranylcarbonyl, thiazolylcarbonyl,indolylcarbonyl, morpholinylcarbonyl, thiomorpholinylcarbonyl,thiomorpholinyl S,S dioxide-carbonyl, piperazinylcarbonyl,piperidinylcarbonyl, pyrrolidinylcarbonyl, pyridylcarbonyl,pyrazolylcarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl,—C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, or —SO₂-phenyl wherein the cyclic groupsare optionally substituted with 1, 2, 3, or 4 groups that areindependently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, NO₂, OH, NH₂,NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, C₁-C₂ haloalkyl or C₁-C₂haloalkoxy.
 7. A compound according to claim 6, wherein L₂ is a bond,—O—(C₁-C₆)alkyl-, —(C₁-C₆)alkyl-O—, —N(R₈)C(O)— (C₁-C₄)alkyl-,—(C₁-C₄)alkyl-C(O)N(R₈)—; wherein R₈ is H, (C₃-C₆)alkyl, benzyl,phenyl-CO—, wherein the phenyl groups are optionally substituted withC₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, NO₂, CF₃, or OCF₃; L₃ is a bond,—(C₁-C₄)alkyl-O—, —O—(C₁-C₄)alkyl, or —(C₁-C₄)alkyl-; and L₄ is—(C₁-C₄)alkyl-, —S(O)_(u)—CH₂—, or -(C₁-C₄)alkyl-S(O)_(u)—CH₂—; whereinu is 0, 1, or
 2. 8. A compound according to claim 7, of the formula


9. A compound according to claim 8, wherein Q is-benzofuranyl-(C₁-C₄)alkyl-phenyl, -dibenzofuranyl-(C₁-C₄)alkyl-phenyl,indolyl, phenyl, benzofuranyl, benzimidazolyl, or dibenzofuranyl, eachof which is optionally substituted with 1, 2, 3, 4, or 5 groups that areindependently C₁-C₆ alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,CF₃, OCF₃, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, or phenyl.10. A compound according to claim 9, wherein R₁ is H, or C₁-C₆ alkyl; R₆is H; at least one of R₂₀ and R₂₁ is H; and L₄ is -(C₁-C₄)alkyl-,—S(O)_(u)—CH₂—, or —CH₂—S(O)_(u)—CH₂—; wherein u is 0, 1, or
 2. 11. Acompound according to claim 10, wherein R₇ is C₁-C₆ alkyl,(C₂-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl,or —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl.
 12. A compound according to claim 10,wherein R₇ is phenyl(C₁-C₄)alkyl, phenyl(C₁-C₆)alkanoyl,benzyloxycarbonyl, benzimidazolylcarbonyl, benzofuranylcarbonyl,thiazolylcarbonyl, indolylcarbonyl, morpholinylcarbonyl,piperazinylcarbonyl, piperidinylcarbonyl, pyrrolidinylcarbonyl, or—SO₂-phenyl wherein the cyclic groups are optionally substituted with 1,2, 3, or 4 groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, NO₂, OH, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, CF₃ orOCF₃.
 13. A compound according to claim 12, wherein Q is-benzofuranyl-(C₁-C₄)alkyl-phenyl, indolyl, phenyl, or dibenzofuranyl,each of which is optionally substituted with 1, 2, 3, 4, or 5 groupsthat are independently C₁-C₆ alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy,halogen, CF₃, OCF₃, NH₂, NH(C₁-C₆)alkyl, or N(C₁-C₆)alkyl(C₁-C₆)alkyl.14. A compound according to claim 13, wherein R₇ is benzyl,phenyl(C₁-C₄)alkanoyl, benzyloxycarbonyl, or —SO₂-phenyl wherein thecyclic groups are optionally substituted with 1, 2, or 3 groups that areindependently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, NO₂, OH, NH₂,NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, CF₃ or OCF₃.
 15. A compoundaccording to claim 1 of the formula:

wherein R₂₀, and R₂₁ are independently selected from H, benzyloxy,benzyl, halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, NO₂, NH₂,NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, NH-phenyl,N(C₁-C₄)alkyl-aryl, —NHSO₂-phenyl, or —N(C₁-C₄ alkyl)SO₂phenyl, whereinthe phenyl group is optionally substituted with 1, 2, 3, or 4 groupsthat are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH, NO₂,C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy.
 16. A compound according to claim 15,wherein R₁ is H, C₁-C₆ alkyl or benzyl; R₇ is phenyl(C₁-C₄)alkyl,phenyl(C₁-C₆)alkanoyl, benzyloxycarbonyl, benzimidazolylcarbonyl,benzofuranylcarbonyl, thiazolylcarbonyl, indolylcarbonyl,morpholinylcarbonyl, piperazinylcarbonyl, piperidinylcarbonyl,pyrrolidinylcarbonyl, or —SO₂-phenyl wherein the cyclic groups areoptionally substituted with 1, 2, 3, or 4 groups that are independentlyhalogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, NO₂, OH, NH₂, NH(C₁-C₆)alkyl,N(C₁-C₆)alkyl(C₁-C₆)alkyl, CF₃ or OCF₃.
 17. A compound according toclaim 16, wherein L₃ is a bond, —CH₂—, or —(C₁-C₂)alkyl-O—; Q is-benzofuranyl-(C₁-C₄)alkyl-phenyl, -pyridyl-(C₁-C₄)alkyl-phenyl,-dibenzofuranyl-(C₁-C₄)alkyl-phenyl, indolyl-(C₁-C₄)alkyl-phenyl,-phenyl-(C₁-C₄)alkyl-benzofuranyl, indolyl, phenyl, benzofuranyl,benzimidazolyl, or dibenzofuranyl, each of which is optionallysubstituted with 1, 2, 3, 4, or 5 groups that are independently C₁-C₆alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, C₁-C₂ haloalkyl,C₁-C₂ haloalkoxy, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, orphenyl; and R₂₀, and R₂, are independently selected from H, benzyloxy,benzyl, halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, NO₂, NH₂,NH(C₁-C₆)alkyl, or N(C₁-C₆)alkyl(C₁-C₆)alkyl.
 18. A method of treatingdiabetes comprising administering a pharmaceutically acceptable amountof a compound of claim 1 to a patient in need of such treatment.
 19. Apharmaceutical composition comprising a compound of claim 1 and at leastone pharmaceutically acceptable solvent, carrier, adjuvant or excipient.20. A compound according to claim 1 that is selected from the groupconsisting ofS-[4′-(2-benzyl-1-benzofuran-3-yl)-6-fluoro-4-nitrobiphenyl-3-yl]-N-(tert-butoxycarbonyl)-L-cysteine;S-[4′-(2-benzyl-1-benzofuran-3-yl)-3-nitrobiphenyl-4-yl]-N-(tert-butoxycarbonyl)-L-cysteine;S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-(tert-butoxycarbonyl)-L-cysteine;3-({[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}sulfinyl)-N-(tert-butoxycarbonyl)-L-alanine;3-({[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}sulfonyl)-N-(tert-butoxycarbonyl)-L-alanine;N-benzoyl-S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-L-cysteine;S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-(3-phenylpropanoyl)-L-cysteine;N-(1H-benzimidazol-5-ylcarbonyl)-S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-L-cysteine;S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-[(4-fluorophenyl)acetyl]-L-cysteine;S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-[(3-nitrophenyl)acetyl]-L-cysteine;S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-(phenylacetyl)-L-cysteine;S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-(1H-indol-5-ylcarbonyl)-L-cysteine;S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-[(4-nitrophenyl)acetyl]-L-cysteine;S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-[(2-nitrophenyl)acetyl]-L-cysteine;S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-[(4-hydroxyphenyl)acetyl]-L-cysteine;N-acetyl-S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-L-cysteine;S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-[(4-methoxyphenyl)acetyl]-L-cysteine;N-[(4-aminophenyl)acetyl]-S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-L-cysteine;N-(tert-butoxycarbonyl)-S-{[4′-(1H-indol-1-yl)biphenyl-4-yl]methyl}-L-cysteine;N-(tert-butoxycarbonyl)-3-({[4′-(1H-indol-1-yl)biphenyl-4-yl]methyl}sulfinyl)-L-alanine;3-({[4′-(1H-indol-1-yl)biphenyl-4-yl]methyl}sulfinyl)-N-(phenylacetyl)-L-alanine;S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-(2-methyl-1,3-thiazol-4-yl)-L-cysteine;S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-[(4-methyl-3-nitrophenyl)sulfonyl]-L-cysteine;S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-(methoxycarbonyl)-L-cysteine;S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-(isobutoxycarbonyl)-L-cysteine;S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-(morpholin-4-ylcarbonyl)-L-cysteine;S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-[(dimethylamino)carbonyl]-L-cysteine;S-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-[(benzyloxy)carbonyl]-L-cysteine;N-(tert-butoxycarbonyl)-3-({4-[(1H-indol-1-ylacetyl)amino]benzyl}sulfonyl)-D-alanine;3-{[4-({[5-(benzyloxy)-1H-indol-1-yl]acetyl}amino)benzyl]sulfonyl}-N-(tert-butoxycarbonyl)-D-alanine;S-{[4′-(1H-indol-1-yl)biphenyl-4-yl]methyl}-N-(methoxycarbonyl)-L-cysteine;S-{[4′-(1H-indol-1-yl)biphenyl-4-yl]methyl}-N-(isobutoxycarbonyl)-L-cysteine;S-{[4′-(1H-indol-1-yl)biphenyl-4-yl]methyl}-N-(morpholin-4-ylcarbonyl)-L-cysteine;methylS-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-(phenylacetyl)-L-cysteinate;methylS-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-N-(3-phenylpropanoyl)-L-cysteinate;S-{[4′-(1H-indol-1-yl)biphenyl-4-yl]methyl}-N-[(3-nitrophenyl)acetyl]-L-cysteine;S-{[4′-(1H-indol-1-yl)biphenyl-4-yl]methyl}-N-(phenylacetyl)-L-cysteine;N-[(dimethylamino)carbonyl]-S-{[4′-(1H-indol-1-yl)biphenyl-4-yl]methyl}-L-cysteine;3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-2-[(pyridine-3-carbonyl)-amino]-propionicacid;N-(tert-butoxycarbonyl)-3-{[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]sulfonyl}-L-alanine;2-tert-Butoxycarbonylamino-4-(4′-dibenzofuran-4-yl-biphenyl-4-ylsulfanyl)-butyricacid;2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethanesulfonyl)-propionicacid;2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-propionicacid;N-[(benzyloxy)carbonyl]-S-{[4′-(1H-indol-1-yl)biphenyl-4-yl]methyl}-L-cysteine;N-(tert-butoxycarbonyl)-S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]-L-cysteine;N-(tert-butoxycarbonyl)-S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]cysteine;N-(tert-butoxycarbonyl)-3-{[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]sulfinyl}alanine;N-(tert-butoxycarbonyl)-3-{[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]sulfonyl}alanine;N-(tert-butoxycarbonyl)-O-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]serine;N-(tert-butoxycarbonyl)-5-(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)norvaline;(4E)-2-[(tert-butoxycarbonyl)amino]-5-(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)pent-4-enoicacid;N-(tert-butoxycarbonyl)-S-(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)homocysteine;2-[(tert-butoxycarbonyl)amino]-4-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)sulfonyl]butanoicacid;N-(tert-butoxycarbonyl)-O-(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)homoserine;N-(tert-butoxycarbonyl)-S-(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)cysteine;N-(tert-butoxycarbonyl)-3-{[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]thio}valine;N-(tert-butoxycarbonyl)-3-{[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]thio}valine;N-(tert-butoxycarbonyl)-S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]cysteine;S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]-N-(3,3-dimethylbutanoyl)cysteine;N-[(tert-butylamino)carbonyl]-S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]cysteine;S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]cysteine;N-[amino(imino)methyl]-S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]cysteine;N-{(Z)-[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}-S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]cysteine;N-benzoyl-S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]cysteine;2-{[(2-{[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]thio}-1-carboxyethyl)amino]carbonyl}benzoicacid;4-[[[1-carboxy-2-[[[4′-(4-dibenzofuranyl)[1,1′-biphenyl]-4-yl]methyl]thio]ethyl]amino]carbonyl]-benzoicacid;S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]-N-(4-nitrobenzoyl)cysteine;N-(4-cyanobenzoyl)-S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]cysteine;S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]-N-(4-fluorobenzoyl)cysteine;S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]-N-(2,4-difluorobenzoyl)cysteine;S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]-N-(2,4,6-trifluorobenzoyl)cysteine;S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]-N-[2-fluoro-4-(trifluoromethyl)benzoyl]cysteine;S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]-N-[2-fluoro-5-(trifluoromethyl)benzoyl]cysteine;S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]-N-(4-methoxybenzoyl)cysteine;S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]-N-(pyridin-3-ylcarbonyl)cysteine;N-phenylglycyl-S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]cysteine;S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]-N-{[3-(trifluoromethyl)phenyl]acetyl}cysteine;S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]-N-[(4-fluorophenyl)acetyl]cysteine;N-[(1-acetyl-5-hydroxypyrrolidin-3-yl)carbonyl]-S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]cysteine;N-[(1-acetylpyrrolidin-3-yl)carbonyl]-S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]cysteine;S-[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]-N-[(1,5-dimethyl-1H-pyrazol-3-yl)carbonyl]cysteine;4-[(2-{[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)methyl]thio}-1-carboxyethyl)amino]-4-oxobutanoicacid;2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphenyl-3-ylsulfanyl)-propionicacid;2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-3-fluoro-biphenyl-4-ylmethylsulfanyl)-propionicacid;2-tert-Butoxycarbonylamino-3-[4-(4,6-diphenyl-pyrimidin-2-yl)-benzylsulfanyl]-propionicacid;3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-2-(4-trifluoromethyl-benzylamino)-propionicacid;3-(2-Acetyl-[1,1′;4′,1″]terphenyl-4″-ylmethylsulfanyl)-2-tert-butoxycarbonylamino-propionicacid;2-tert-Butoxycarbonylamino-3-(2-methoxy-[1,1′;4′,1″]terphenyl-4″-ylmethylsulfanyl)-propionicacid;2-tert-Butoxycarbonylamino-3-(4′-dibenzothiophen-4-yl-biphenyl-4-ylmethylsulfanyl)-propionicacid;2-tert-Butoxycarbonylamino-3-[4-(6-dibenzofuran-4-yl-pyridin-3-yl)-benzylsulfanyl]-propionicacid;2-tert-Butoxycarbonylamino-3-[4-(2-dibenzofuran-4-yl-thiazol-5-yl)-benzylsulfanyl]-propionicacid;2-tert-Butoxycarbonylamino-3-[4-(5-dibenzofuran-4-yl-6-methyl-pyridin-2-yl)-benzylsulfanyl]-propionicacid;2-tert-Butoxycarbonylamino-4-(4′-dibenzofuran-4-yl-biphenyl-4-yloxy)butryicacid;2-tert-Butoxycarbonylamino-4-(4′-dibenzofuan-4-yl-biphenyl-4-ylsulfanyl)-butryicacid;2-tert-Butoxycarbonylamino-4-(4′-dibenzofuan-4-yl-biphenyl-4-ylsulfanyl)-butryicacid methyl ester2-tert-Butoxycarbonylamino-4-(4′-dibenzofuan-4-yl-biphenyl-4-ylsulfanyl)-butryicacid2-tert-Butoxycarbonylamino-5-(4′-dibenzofuran-4-yl-biphen-4-yl)-5-pentenoicacid2-tert-Butoxycarbonylamino-5-(4′-dibenzofuran-4-yl-biphen-4-yl)-5-pentenoicacid methyl ester2-tert-Butoxycarbonylamino-5-(4′-dibenzofuran-4-yl-biphen-4-yl)-5-pentenoicacid2-tert-Butoxycarbonylamino-5-(4′-dibenzofuran-4-yl-biphen-4-yl)-pentanoicacid2-tert-Butoxycarbonylamino-5-(4′-dibenzofuran-4-yl-biphen-4-yl)-pentanoicacid methyl ester;2-tert-Butoxycarbonylamino-5-(4′-dibenzofuran-4-yl-biphen-4-yl)-pentanoicacid;2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-yl)-propanoicacid;2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-yl)-propanoicacid methyl ester;2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-yl)-propanoicacid;2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-ylsulfanyl)-propanoicacid;2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-ylsulfanyl)-propanoicacid methyl ester;2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-ylsulfanyl)-propanoicacid;2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-ylmethylsulfanyl)-3,3-dimethylpropanoicacid; Example2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-ylmethylsulfanyl)-3,3-dimethylpropanoicacid methyl ester;2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-ylmethoxy)propanoicacid;2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-ylmethyloxy)-propanoicacid methyl ester;2-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-ylmethyloxy)-propanoicacid;2-Benzyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)phenyl]-benzofuran;and pharmaceutically acceptable salts thereof.